TW201524990A - Substituted nucleosides, nucleotides and analogs thereof - Google Patents

Abstract

Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Picornavirus and/or Flaviviridae infection with one or more nucleosides, nucleotides and nucleotide analogs.

Description

Substituted nucleosides, nucleotides and the like By incorporating any prior application

For example, any and all applications for identifying foreign or national priority in the information sheet or request filed with this application are hereby incorporated by reference in the entirety of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of

This application is in the fields of chemistry, biochemistry and medicine. More specifically, disclosed herein are nucleoside, nucleotide, and nucleotide analogs, including pharmaceutical compositions of one or more nucleosides, nucleotides, and/or nucleotide analogs, and methods for their synthesis. Also disclosed herein are methods of treating diseases and/or conditions using nucleoside, nucleotide and/or nucleotide analogs, either alone or in combination with one or more other agents.

Nucleoside analogs are compounds that have demonstrated antiviral and anticancer activity both in vitro and in vivo, and have thus become the subject of extensive research on the treatment of viral infections. Nucleoside analogs are generally therapeutically inert compounds which are converted by the host or viral enzyme to their corresponding active antimetabolites, which in turn inhibit the polymerase associated with viral or cell proliferation. Activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and/or in combination with other metabolic processes.

Some embodiments disclosed herein relate to a compound of formula (I) or a pharmaceutically acceptable compound thereof Accept the salt. Other embodiments disclosed herein pertain to a compound of formula (II) or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein are directed to methods of ameliorating and/or treating picornavirus infections, which can comprise administering to an individual identified as having a picornavirus infection an effective amount of one or more of Formula (I) and/or A compound of formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of formula (I) and/or formula (II) or a pharmaceutically acceptable salt thereof. Other embodiments described herein are directed to the use of one or more compounds of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, for use in the manufacture and/or treatment of picornavirus infections. Pharmacy. Other embodiments described herein are those relating to one or more compounds of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, or comprising one or more compounds of formula (I) and / or (II) or a medicament thereof A pharmaceutical composition of a salt that is acceptable for use in ameliorating and/or treating picornavirus infection.

Some embodiments disclosed herein are directed to a method of ameliorating and/or treating a picornavirus infection, which can comprise subjecting a cell infected with a picornavirus to an effective amount of one or more compounds described herein (eg, Formula (I) And/or (II) a compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising one or more compounds described herein, or a pharmaceutically acceptable salt thereof, is contacted. Other embodiments described herein are directed to the use of one or more compounds described herein (eg, a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in manufacturing for improvement and/or Or treating an agent for picornavirus infection, the improvement and/or treatment can comprise contacting a cell infected with the picornavirus with an effective amount of the compound. Other embodiments described herein pertain to one or more compounds described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) or include one or more compounds described herein or a pharmaceutical thereof A pharmaceutical composition of a salt that is acceptable for use in ameliorating and/or treating picornavirus infection by contacting cells infected with picornavirus with an effective amount of the compound.

Some embodiments disclosed herein relate to an inhibition of picornavirus replication A method, which may comprise, or an effective amount of one or more of the compounds described herein (eg, a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof) or a pharmaceutically acceptable salt thereof Or a pharmaceutical composition of a plurality of the compounds described herein, or a pharmaceutically acceptable salt thereof, is contacted. Other embodiments described herein are directed to the use of one or more compounds described herein (e.g., a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a small ribose A nucleic acid viral replication agent, the inhibition comprising contacting a cell infected with a picornavirus with an effective amount of the compound. Other embodiments described herein pertain to one or more compounds described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) or include one or more compounds described herein or a pharmaceutical thereof A pharmaceutical composition of a salt that is acceptable for use in inhibiting picornavirus replication by contacting cells infected with picornavirus with an effective amount of the compound. In some embodiments, the picornavirus can be selected from the group consisting of a rhinovirus, a hepatitis A virus, a coxasackie virus, and an enterovirus.

Some embodiments disclosed herein are directed to methods of ameliorating and/or treating Flaviviridae virus infection, which can comprise administering an effective amount to one or more formula (I) to an individual identified as having a Flaviviridae viral infection. And/or (II) a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of one or more compounds of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a Flaviviridae virus for the improvement and/or treatment of Infected agent. Other embodiments described herein are those relating to one or more compounds of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, or comprising one or more compounds of formula (I) and / or (II) or a medicament thereof A pharmaceutical composition of a salt that is acceptable for use in ameliorating and/or treating a Flaviviridae viral infection.

Some embodiments disclosed herein are directed to a method of ameliorating and/or treating a Flaviviridae viral infection, which can comprise causing a cell infected with a Flaviviridae virus with an effective amount of one or more compounds described herein (eg, Formula (I) And/or (II) a compound or a pharmaceutically acceptable compound thereof Salt) or a pharmaceutical composition comprising one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein are directed to the use of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for ameliorating and/or treating a Flaviviridae viral infection, the improvement and / or treatment can include contacting a cell infected with a Flaviviridae virus with an effective amount of the (etc.) compound. Other embodiments described herein pertain to one or more compounds described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) or include one or more compounds described herein or a pharmaceutical thereof A pharmaceutical composition of a salt that is acceptable for use in ameliorating and/or treating a Flaviviridae viral infection by contacting a cell infected with a Flaviviridae virus with an effective amount of the compound.

Some embodiments disclosed herein are directed to a method of inhibiting replication of a Flaviviridae virus, which can comprise causing a cell infected with a Flaviviridae virus with an effective amount of one or more compounds described herein (eg, Formula (I) and/or ( II) a compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising one or more compounds described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein are directed to the use of one or more compounds described herein (eg, a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a flavivirus The agent for replicating the virus, the inhibition comprising contacting the cells infected with the Flaviviridae virus with an effective amount of the compound. Other embodiments described herein pertain to one or more compounds described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) or include one or more compounds described herein or a pharmaceutical thereof A pharmaceutical composition of a salt that is acceptable for use in inhibiting replication of the Flaviviridae virus by contacting a cell infected with a Flaviviridae virus with an effective amount of the compound. In some embodiments, the Flaviviridae virus may be selected from the group consisting of hepatitis C virus, West Nile virus, yellow fever virus, dengue virus from the Flaviviridae family of viruses. And encephalitis virus.

Figure 1 shows an example HCV protease inhibitor.

Figure 2 shows an example nucleoside HCV polymerase inhibitor.

Figure 3 shows an example non-nucleoside HCV polymerase inhibitor.

Figure 4 shows an example NS5A inhibitor.

Figure 5 shows an example of other antiviral agents.

6 shows an example (CC) compound and its α- ^{thiotriphosphate} , wherein R ^CC1 , R ^CC2 , R ^CC3a , R ^CC3b , R ^CC4 , R ^CC5 , R ^CC6 , R ^CC7 , R ^CC8 , R ^CC9 and B ^{CC1 is} as defined herein.

7 shows a compound of formula (AA) wherein R ^1AA , R ^2AA , R ^3AA , R ^4AA , R ^{5AA ,} and B ^{1AA are} as defined herein.

8 shows a compound of the formula (BB) wherein R ^BB1 , R ^BB2 , R ^BB3 , R ^BB4 , R ^BB5 , R ^BB6 , R ^BB7 , R ^BB8 , X ^BB and B ^{BB1 are} as defined herein.

Figure 9 shows a compound of the formula (I) wherein Z ¹ , O ¹ , R ^1A , R ^2A , R ^3A , R ^4A , R ^5A , B ^1A , Z ^1B , R ^1B , Z ² , O ² , R ^1C , R ^2C , R ^3C , R ^4C , R ^5C , B ^1C , Z ^1D and R ^{1D are} as defined herein.

The virus in the picornavirus family is a non-enveloped sense single-stranded spherical RNA virus with an icosahedral capsid. The picornavirus genome is about 7-8 kilobases long and has an IRES (internal ribosome entry site). These viruses are polyadenylated at the 3' end and have a VPg protein at the 5' end instead of capping. The genus of the picornavirus family includes the Aphthovirus, the Aquamavirus, the Avihepatovirus, the Cardiovirus, the Cosavirus, and the genus Dicipivirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Megrivirus, Double Echovirus Genus (Parechovirus), Rhinovirus, Salivirus, Sapelovirus, Senecavirus, Czech (Teschovirus) and Tremovirus.

Enterovirus spreads through the fecal-oral route and/or through the aerosols of small droplets of the respiratory tract and is highly contagious. Enterovirus genus includes several types, including: enterovirus A, enterovirus B, enterovirus C, enterovirus D, enterovirus E, enterovirus F, enterovirus G, enterovirus H, enterovirus J, rhinovirus A, nasal Virus B and rhinovirus C. The aforementioned enterovirus types are the following serotypes: poliovirus, rhinovirus, coxsackie virus, echovirus and enterovirus.

Rhinovirus is the cause of a cold. Rhinoviruses are named for their transmission through the respiratory tract and replication in the nose. Individuals can infect many rhinoviruses during their lifetime because they are immune to each serotype. Therefore, each serotype can cause a new infection.

Hepatitis A infection is the result of infection with hepatitis A virus. Liver virus is transmitted through the fecal-oral route. It can be transmitted by individuals-individuals by ingesting contaminated food or water or by direct contact with infectious individuals.

Double echovirus includes human double echovirus 1 (Echovirus 22), human double echovirus 2 (Echovirus 23), human double echovirus 3, human double echovirus 4, human double echovirus 5 and human double echovirus 6.

The virus of the Flaviviridae is a coated single-sense spherical RNA virus having an icosahedral shape capsid. These viruses are polyadenylated at the 5' end but lack a 3' polyadenylation tail. The genus of the Flaviviridae includes the genus Flavivirus, the genus Pestivirus, and the genus Hepatitis C virus. Flaviviridae viruses are mainly transmitted by insect vectors and are usually transmitted by mosquitoes and ticks.

The genus Flavivirus includes several encephalitis viruses (eg, Japanese encephalitis virus (JEV), St. Louis encephalitis virus (SLEV) and tick-borne encephalitis virus (TBEV)), and dengue virus 1-4 (DENV). West Nile virus (WNV) and yellow fever virus (YFV). Viruses in the genus Pestivirus include bovine viral diarrhea virus 1, bovine viral diarrhea virus 2 and typical swine fever virus.

definition

Unless otherwise defined, all technical and scientific terms used herein have the same as The general practitioner usually understands the same meaning. All patents, applications, published applications, and other publications referred to herein are incorporated by reference in their entirety. Unless otherwise stated, where a term has a plurality of definitions in this document, the definition in this section prevails.

As used herein, such as, but not limited to, R ¹ , R ² , R ³ , R ⁴ , R ^5A , R ^5B , R ^6A , R ^6B , R ^6C , R ^6D , R ^6E , R ^6F , R ^6G , R ^6H , R ^7A , R ^7B , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ^A1 , R ^A2 , R ^A3 and Any "R" group of R ^A4 represents a substituent which may be attached to a specified atom. The R group can be substituted or unsubstituted. If two "R" groups are described as "bonded together", the R group and the atom to which it is attached may form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, but not limited to, if R ^a and R ^{b of the} NR ^a R ^b group are indicated as "bonded together", it means that they are covalently bonded to each other to form a ring:

In addition, if two "R" groups are described as "bonded together" to the atoms to which they are attached to form a ring, the R group is not limited to the previously defined variables or substituents.

Whenever a group is described as "optionally substituted", the group may be unsubstituted or substituted by one or more of the specified substituents. Likewise, when a group is described as "unsubstituted or substituted", if substituted, the substituent may be selected from one or more of the specified substituents. If no substituent is specified, it means that the "optionally substituted" or "substituted" group may be substituted by one or more groups individually and independently selected from: alkyl, alkenyl, alkyne , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl), (heterocyclyl) alkyl, hydroxy, alkoxy , mercapto, cyano, halogen, thiocarbonyl, O-amine, sulfonyl, N-amine, thiol, O-thiocarbamyl, N-thiocarbamyl, C-nonylamine, N-decylamine, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxy, isocyanate, thiocyano, isothiocyanato, nitro, azide, decyl, Times Sulfonyl, fluorenylene, fluorenyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino, amine, monosubstituted amine and disubstituted amine.

As used herein, "C _a to C _b " in which "a" and "b" are integers mean the number of carbon atoms in an alkyl group, an alkenyl group or an alkynyl group; or a cycloalkyl group, a cycloalkenyl group, an aryl group, The number of carbon atoms in the ring of the heteroaryl or heterocyclic group. That is, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl ring, a cycloalkenyl ring, an aryl ring, a heteroaryl ring or a heterocyclic ring may contain "a" to "b" (including a, b) a carbon atom. Thus, for example, "C ₁ to C ₄ alkyl" means that all alkyl groups have from 1 to 4 carbons, that is, CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, ( CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH(CH ₃ )- and (CH ₃ ) ₃ C-. If "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkylcycloalkenyl, aryl, heteroaryl or heterocyclic group, the broadest of these definitions should be assumed range.

As used herein, "alkyl" refers to a straight or branched chain hydrocarbon chain comprising a fully saturated (no double or bonded) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" means each integer in a given range; for example, "1 to 20 carbon atoms" means an alkane The group may be composed of up to and including 20 carbon atoms, one carbon atom, two carbon atoms, three carbon atoms, etc., but this definition also encompasses the occurrence of the term "alkyl group" in which no numerical range is specified. The alkyl group may also be an equivalent size alkyl group having from 1 to 10 carbon atoms. The alkyl group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group of the compound may be named "C ₁ -C ₄ alkyl" or the like. By way of example only, "C ₁ -C ₄ alkyl" means that one to four carbon atoms are present in the alkyl chain, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and n-butyl. Base, isobutyl, second butyl and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. The alkyl group may be substituted or unsubstituted.

As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. Examples of alkenyl groups include alkenyl, vinylmethyl and vinyl. The alkenyl group may be unsubstituted or substituted.

As used herein, "alkynyl" refers to an alkyl group containing one or more reference bonds in a straight or branched hydrocarbon chain. Examples of alkynyl groups include ethynyl and propynyl. An alkynyl group can be unsubstituted or substituted.

As used herein, "cycloalkyl" refers to a fully saturated (no double or para-bonded) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused manner. The cycloalkyl group may have 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. The cycloalkyl group can be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; but if more than one double bond is present, the double bond cannot be formed throughout all of the rings. Completely non-localized pi-electron system (otherwise the group will be "aryl" as defined herein). When composed of two or more rings, the rings may be joined together in a fused manner. The cycloalkenyl group may have 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. The cycloalkenyl group may be unsubstituted or substituted.

As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system having a fully delocalized π-electron system throughout all rings (including the condensation of two carbon rings sharing a chemical bond) Ring system). The number of carbon atoms in the aryl group can vary. For example, the aryl group can be a C ₆ -C ₁₄ aryl group, a C ₆ -C ₁₀ aryl group or a C ₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

As used herein, "heteroaryl" refers to a monocyclic, bicyclic, and tricyclic aromatic ring system containing one or more heteroatoms (eg, 1 to 5 heteroatoms) (having a ring of fully delocalized pi-electron systems) The heteroatoms are not carbon elements, including but not limited to nitrogen, oxygen and sulfur. The number of atoms in the ring of the heteroaryl group can vary. For example, a heteroaryl group can contain from 4 to 14 atoms in the ring, from 5 to 10 atoms in the ring, or from 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, pyridazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2, 4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, oxazole, pyrazole, benzopyrazole Azole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, acridine, quinoline, isoquine Porphyrin, quinazoline, quinoxaline, Porphyrin and triazine. The heteroaryl group may be substituted or unsubstituted.

As used herein, "heterocyclyl" means three, four, five, six, seven, eight, nine, ten, up to 18 membered monocyclic, bicyclic and tricyclic ring systems in which a carbon atom and 1 to 5 heteroatoms Together they form the ring system. The heterocycle may optionally contain one or more unsaturated bonds, however the or such linkages are positioned in such a way that a completely non-localized pi-electron system does not occur throughout the ring. Heteroatoms are elements other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. The heterocyclic ring may further contain one or more carbonyl or thiocarbonyl functional groups such that the definition includes pendant oxygen systems and sulfur based systems such as indoleamines, lactones, cyclic quinone imines, cyclic sulfoximines and Cyclic urethane. When composed of two or more rings, the rings may be joined together in a fused manner. Furthermore, any nitrogen in the heterocyclic or heteroalicyclic group can be quaternized. The heterocyclic group may be unsubstituted or substituted. Examples of such "heterocyclic groups" include, but are not limited to, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxyheterocycle. Pentane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxetane, 1, 3-oxathiolane, 1,3-diphene, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H- 1,2-oxazine, maleimide, amber imine, barbituric acid, thiobarbituric acid, two-side oxypiperazine, beta-urea, dihydrouracil, three Oxane, hexahydro-1,3,5-triazine, imidazoline, imidazolium, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazole, Morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidinedione, 4-piperidone, pyrazoline, pyrazole, 2-side Oxypyrrolidinium, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholinium, thiamorpholinium and their benzo-fused analogs (eg benzoyl) Imidazolinedione, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

As used herein, "aralkyl" and "aryl (alkyl)" refer to an aryl group attached as a substituent via a lower alkylalkylene group. The lower alkylalkyl and aryl groups of the aryl (alkyl) group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl (alkyl).

As used herein, "heteroaralkyl" and "heteroaryl (alkyl)" refers to a heteroaryl group attached as a substituent via a lower carbon alkylene group. The lower arylalkyl and heteroaryl groups of the heteroaryl (alkyl) group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl (alkyl), 3-thienyl (alkyl), furyl (alkyl), thienyl (alkyl), pyrrolyl (alkyl), pyridyl (alkane) And pyrazolyl (alkyl), imidazolyl (alkyl) and benzo-fused analogs thereof.

"(heteroalicyclic)alkyl" and "(heterocyclyl)alkyl" mean a heterocyclic or heteroalicyclic group as a substituent via a lower alkylene group. The lower carbon alkyl and heterocyclic groups of the heterocyclic group (alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-piperidin-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H- Thioppyran-4-yl (methyl) and 1,3-thiacyclo-4-yl (methyl).

The "low carbon alkylene group" is a linear -CH ₂ -pyred group which forms a bond connecting a molecular fragment via its terminal carbon atom. Examples include, but are not limited to, methylene (-CH ₂ -), ethyl (-CH ₂ CH ₂ -), propyl (-CH ₂ CH ₂ CH ₂ -), and butyl (-CH _{2 )} CH ₂ CH ₂ CH ₂ -). The lower carbon alkylene group may be substituted by replacing one or more hydrogens of the lower carbon alkyl group with a substituent listed under the definition of "substituted".

As used herein, "alkoxy" refers to the formula -OR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, as defined herein, Aralkyl, heteroaryl (alkyl) or heterocyclic (alkyl). A non-limiting list of alkoxy groups are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, second butoxy Base, third butoxy, phenoxy and benzhydryloxy. The alkoxy group may be substituted or unsubstituted.

As used herein, "mercapto" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaryl (alkyl) Or a heterocyclic group (alkyl group) as a substituent is bonded via a carbonyl group. Examples include a decyl group, an ethyl fluorenyl group, a propyl fluorenyl group, a benzamidine group, and a propylene group. The thiol group may be substituted or unsubstituted.

As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. The hydroxyalkyl group may be substituted or unsubstituted.

As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (eg, monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl groups may be substituted or unsubstituted.

As used herein, "haloalkoxy" refers to an O-alkyl group in which one or more hydrogen atoms are replaced by a halogen (eg, a monohaloalkoxy group, a dihaloalkoxy group, and a trihaloalkoxy group). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy . Haloalkoxy groups may be substituted or unsubstituted.

"Sulfosyl" means a radical "-SR" wherein R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl Alkyl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The sulfenyl group can be substituted or unsubstituted.

"Alkenylene" means a radical "-S(=O)-R" wherein R may be as defined for sulfenyl. The fluorenylene group may be substituted or unsubstituted.

"Sulfonyl" means a "SO ₂ R" group wherein R may be as defined for sulfenyl. The sulfonyl group may be substituted or unsubstituted.

"O-carboxy" refers to a "RC(=O)O-" group, wherein R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, as defined herein, Heteroaryl, heterocyclic, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The O-carboxy group may be substituted or unsubstituted.

The terms "ester" and "C-carboxy" refer to a "-C(=O)OR" group, wherein R may be the same as defined for the O-carboxy group. The ester and C-carboxy group may be substituted or unsubstituted.

"Thiocarbonyl" means a "-C(=S)R" group wherein R may be as defined for the O-carboxy group. The thiocarbonyl group may be substituted or unsubstituted.

"Trihalomethanesulfonyl" refers to a "X ₃ CSO ₂ -" group wherein each X is a halogen.

"Trihalomethanesulfonamide" means a group of "X ₃ CS(O) ₂ N(R _A )-" wherein each X is halogen and R _A is hydrogen, alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl).

As used herein, the term "amino" means -NH ₂ group.

As used herein, the term "hydroxy" refers to an -OH group.

"Cyano" means a "-CN" group.

As used herein the term "azido" group refers to -N _3.

"Isocyanate group" means a "-NCO" group.

"Thiocyano" means a "-CNS" group.

"Isothiocyanato" means a "-NCS" group.

"巯基" means the "-SH" group.

"Carbonyl" means a C=O group.

"S-sulfonylamino" means a "-SO ₂ N(R _A R _B )" group, wherein R _A and R _B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The S-sulfonylamino group may be substituted or unsubstituted.

"N-sulfonylamino" means a "RSO ₂ N(R _A )-" group wherein R and R _A are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The N-sulfonylamino group may be substituted or unsubstituted.

"O-Aminomethyl" refers to a "-OC(=O)N(R _A R _B )" group, wherein R _A and R _B are independently hydrogen, alkyl, alkenyl, alkynyl, and ring. Alkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The O-amine carbenyl group may be substituted or unsubstituted.

"N-Aminomethyl" refers to a "ROC(=O)N(R _A )-" group, wherein R and R _A are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkenyl, aryl, heteroaryl, heteroalicyclic, aryl (alkyl), heteroaryl (alkyl) or heterocyclic (alkyl). The N-amine carbenyl group may be substituted or unsubstituted.

"O-Thiocarbamimidyl" means a "-OC(=S)-N(R _A R _B )" group, wherein R _A and R _B are independently hydrogen, alkyl, alkenyl, alkyne Or a cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclic (alkyl) group. The O-thioaminecarbamyl group may be substituted or unsubstituted.

"N-Thiocarbamoyl" means a "ROC(=S)N(R _A )-" group, wherein R and R _A are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkane A group, a cycloalkenyl group, an aryl group, a heteroaryl group, a heterocyclic group, an aryl (alkyl group), a heteroaryl (alkyl group) or a heterocyclic group (alkyl group). The N-thioaminecarbamyl group may be substituted or unsubstituted.

"C-Amino" refers to a "-C(=O)N(R _A R _B )" group, wherein R _A and R _B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkane A group, a cycloalkenyl group, an aryl group, a heteroaryl group, a heterocyclic group, an aryl (alkyl group), a heteroaryl (alkyl group) or a heterocyclic group (alkyl group). The C-guanamine group may be substituted or unsubstituted.

"N-Amino" refers to a "RC(=O)N(R _A )-" group wherein R and R _A are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or ring. Alkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The N-guanidinyl group may be substituted or unsubstituted.

The term "halogen atom" or "halogen" as used herein means any of the radiation-stable atoms of the seventh row of the periodic table, such as fluorine, chlorine, bromine and iodine.

When the number of substituents is not illustrated (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" can include one or more of the same or different halogens. As another example, "C ₁ -C ₃ alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three atoms.

As used herein, unless otherwise indicated, abbreviations for any protecting group, amino acid, and other compounds are consistent with their common usage, recognized abbreviations, or the IUPAC-IUB Biochemical Nomenclature Commission (see Biochem. 11:942-944 (1972). ).

As understood by those skilled in the art, the term "nucleoside" is used herein in its ordinary meaning and refers to the attachment of a pentose moiety or a modified pentose moiety, optionally substituted, to a heterocycle via an N-glycosidic linkage. A compound consisting of a base or a tautomer thereof, such as via a 9-position of a purine base or a 1 position of a pyrimidine base. Examples include, but are not limited to, nucleosides comprising a ribose moiety and deoxynucleosides comprising a deoxyribose moiety. The modified pentose moiety is a pentose moiety in which the oxygen atom has been replaced by carbon and/or the carbon has been replaced by sulfur or an oxygen atom. A "nucleoside" is a monomer that can have a substituted base and/or a sugar moiety. In addition, nucleosides can be incorporated into larger DNA and/or RNA polymers and oligomers. In some cases, the nucleoside can be a nucleoside analog drug.

The term "nucleotide" is used herein in its ordinary meaning as understood by those skilled in the art and refers to a nucleoside having, for example, a phosphate that binds to the pentose moiety at the 5' position.

As used herein, the term "heterocyclic base" refers to an optionally substituted nitrogen-containing heterocyclic group which may be attached to an optionally substituted pentose moiety or a modified pentose moiety. In some embodiments, the heterocyclic base can be selected from optionally substituted purine bases, optionally substituted pyrimidine bases, and optionally substituted triazole bases (eg, 1,2,4-triazole). ). The term "purine base" is used herein in its ordinary meaning as understood by those skilled in the art and includes its tautomers. Similarly, the term "pyrimidine base" is used herein in its ordinary meaning as understood by those skilled in the art, and includes its tautomers. A non-limiting list of bases that have been substituted as appropriate includes sputum, adenine, guanine, hypoxanthine, scutellaria, scutellaria, 7-alkylguanine (eg, 7-methylguanine), cocoa Beanine, caffeine, uric acid and isoguanine. Examples of pyrimidine bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil, and 5-alkylcytosine (e.g., 5-methylcytosine). An example of a triazole base which is optionally substituted is 1,2,4-triazole-3-carboxamide. Other non-limiting examples of heterocyclic bases include diamino hydrazine, 8-sided oxy-N ⁶ -alkyl adenine (eg, 8-sided oxy-N ⁶ -methyl adenine), 7-deaza Astragalus, 7-deazaguanine, 7-deazadenine, N ⁴ , N ⁴ -B-bridged cytosine, N ⁶ ,N ⁶ -B bridge-2,6-diamino guanidine, 5 -halo-uracils (e.g., 5-fluorouracil and 5-bromouracil), pseudoisomers, isocytosines, isoguanines, and other heterocyclic bases as described in U.S. Patent Nos. 5,432,272 and 7,125,855, The patents are hereby incorporated by reference for their purpose for the purpose of the disclosure of the disclosure of the same. In some embodiments, a heterocyclic base may optionally be substituted with an amine or enol protecting group.

The term "-N-linked amino acid" refers to an amino acid that is attached to a specified moiety via a backbone amino group or a monosubstituted amine group. When the amino acid is linked in the form of an -N-bonded amino acid, one of the hydrogens of a portion of the main chain amine group or a monosubstituted amine group is absent and the amino acid is linked via nitrogen. The N-linked amino acid can be substituted or unsubstituted.

The term "-N-linked amino acid ester derivative" means an amino acid in which a main chain carboxylic acid group has been converted into an ester group. In some embodiments, the ester group has a formula selected from the group consisting of alkyl-OC(=O)-, cycloalkyl-OC(=O)-, aryl-OC(=O)-, and aryl (alkane) Base) -OC(=O)-. A non-limiting list of ester groups includes the following substituted and unsubstituted forms: methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, Isopropyl-OC(=O)-, n-butyl-OC(=O)-, isobutyl-OC(=O)-, tert-butyl-OC(=O)-, neopentyl-OC (=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, benzene Base-OC(=O)-, benzyl-OC(=O)-, and naphthyl-OC(=O)-. The N-bonded amino acid ester derivative may be substituted or unsubstituted.

The term "-O-linked amino acid" refers to an amino acid attached to a specified moiety via a hydroxyl group derived from a carboxylic acid group of its main chain. When the amino acid is attached to the -O-bonded amino acid, it is from Hydrogen in a portion of the hydroxyl group of the main chain carboxylic acid group is absent and the amino acid is linked via oxygen. The O-linked amino acid may be substituted or unsubstituted.

As used herein, the term "amino acid" refers to any amino acid (both standard and non-standard amino acids) including, but not limited to, alpha-amino acids, beta-amino acids, gamma-amino groups. Acid and δ-amino acid. Examples of suitable amino acids include, but are not limited to, alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, serine , tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hydroxyresinamine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta- Alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.

The term "phosphorothioate" refers to the formula a compound, in its protonated form (eg and And its tautomers (such as ).

As used herein, the term "phosphate" is used in its ordinary sense as understood by those skilled in the art and includes its protonated form (eg, and ). As used herein, the terms "monophosphate", "diphosphate" and "triphosphate" are used in their ordinary meaning as understood by those skilled in the art and include protonated forms.

The term "protecting group" as used herein refers to any atom or group of atoms added to a molecule to prevent an existing group in the molecule from undergoing an undesirable chemical reaction. Examples of protecting group moieties are described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd Ed., John Wiley & Sons, 1999, and JFW McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, all of which disclose suitable protecting groups. The limited purpose is incorporated herein by reference. The protecting moiety can be selected such that it is stable to certain reaction conditions and is readily removed at a suitable stage using methods known in the art. A non-limiting list of protecting groups includes benzyl; substituted benzyl; alkylcarbonyl and alkoxycarbonyl (eg, third butoxycarbonyl (BOC), ethionyl or isobutyl); arylalkyl Carbonyl and arylalkoxycarbonyl (e.g., benzyloxycarbonyl); substituted methyl ether (e.g., methoxymethylether); substituted diethyl ether; substituted benzyl ether; tetrahydropyranyl Ether; decyl group (eg, trimethyl decyl, triethyl decyl, triisopropyl decyl, tert-butyl dimethyl decyl, triisopropyl decyloxymethyl, [2- (three) Methyl decyl) ethoxy] methyl or tert-butyldiphenyl decyl) ester (eg benzoate); carbonate (eg methoxymethyl carbonate); sulfonate (eg Tosylate or mesylate); acyclic ketal (eg dimethyl acetal); cyclic ketal (eg 1,3-dioxane, 1,3-dioxolane and a cyclic ketal as described herein; acyclic acetal; a cyclic acetal (such as a cyclic acetal as described herein); an acyclic hemiacetal; a cyclic hemiacetal; Thiol ketal (eg 1,3-dithiane or 1,3-di) Heterocyclic pentane); orthoester (such as the orthoester described herein); and triarylmethyl (eg, trityl; monomethoxytrityl (MMTr); 4, 4'- Dimethoxytrityl (DMTr); 4,4',4"-trimethoxytrityl (TMTr); and the triarylmethyl group described herein).

The term "pharmaceutically acceptable salts" refers to salts of compounds which do not cause significant irritation to the organism to which they are administered and which do not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of a compound. Pharmaceutical salts can be obtained by reacting a compound with a mineral acid such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as an aliphatic or aromatic carboxylic acid or a sulfonic acid such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, Obtained by the reaction of sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid or naphthalenesulfonic acid. Pharmaceutical salts can also form salts by reacting the compound with a base such as an ammonium salt; an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base such as dicyclohexylamine, N- a salt of methyl-D-glucosamine, cis (hydroxymethyl)methylamine, C ₁ -C ₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine); and with an amino acid such as spermine Obtained from the salt of acid and lysine).

Terms and phrases used in the present application, particularly in the scope of the appended claims, and variations thereof, are to be considered as open and limited. As used in the preceding examples, the term "comprising" is to be understood to mean "including but not limited to" or the like. The term "comprising" as used herein is synonymous with "including", "containing" or "characterized". And is included or open and does not exclude other unlisted elements or method steps; the term "having" should be interpreted as "having at least"; the term "including" should be interpreted as "including (but not limited to)"; "Examples" are used to provide illustrative examples of the items in question, and are not exhaustive or to limit their list; and terms such as "better", "better", "desired" or "desirable" and The use of words having similar meanings should not be construed as meaning that certain features are critical, essential, or even essential to the structure or function of the invention, but are merely intended to emphasize that alternative or other features may or may not be used in a particular implementation. In the example. In addition, the term "comprising" should be interpreted synonymously with the phrase "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the steps, but may include other steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the features or components, but may also include other features or components. Also, unless explicitly stated otherwise, a group of items connected with the conjunction "and" is not to be construed as requiring that each of the items is present in the group and should be understood as "and/or". Similarly, unless explicitly stated otherwise, a group of items connected with the conjunction "or" should not be construed as requiring a mutual exclusivity in the group, but rather as "and/or".

With respect to the use of any plural and/or singular terms in this context, those skilled in the art can change from plural to singular and/or from singular to plural, as appropriate. A variety of singular/plural permutations can be explicitly set forth herein for clarity. The indefinite article "a" or "an" does not exclude the plural. A single processor or other component can fulfill the functions of several items described in the scope of the patent application. The fact that certain measurements are recited in mutually different sub-technical solutions does not indicate that a combination of such measurements is not advantageous. Any reference mark in the scope of patent application shall not be considered as a limitation.

It will be understood that in any of the compounds described herein having one or more pairs of palmar centers, the centers may independently have an R configuration or an S configuration or a mixture thereof if the absolute stereochemistry is not explicitly specified. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomeric, diastereomeric, or stereoisomeric mixtures. In addition, it is to be understood that in any of the compounds described herein having one or more double bonds which produce a geometric isomer which may be defined as E or Z, each double bond may independently be E or Z or a mixture thereof.

Likewise, it is to be understood that all tautomeric forms are also intended to be included in any of the recited compounds. For example, all tautomers of phosphate and phosphorothioate groups are intended to be included. Examples of tautomers of phosphorothioates include the following: , , and . In addition, all tautomers of heterocyclic bases known in the art are intended to include tautomers of natural and non-natural purine bases and pyrimidine bases.

It will be understood that when the compounds disclosed herein have less than a valence, the valence will be filled with hydrogen or an isotope thereof (e.g., hydrogen-1 (oxime) and hydrogen-2 (oxime)).

It will be understood that the compounds described herein may be isotopically labeled. The use of isotopes such as hydrazine to obtain certain therapeutic advantages resulting from greater metabolic stability, such as increased In vivo half-life or reduced dose requirements. Each chemical element represented in the structure of the compound may include any isotope of the element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in a compound. At any position of the compound in which a hydrogen atom may be present, the hydrogen atom may be any isotopes of hydrogen including, but not limited to, hydrogen-1 (hydrazine) and hydrogen-2 (helium). Thus, reference to a compound encompassed herein encompasses all potential isotopic forms, unless the context clearly indicates otherwise.

It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, including different crystal packing configurations of the same elemental composition of the compounds), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in a solvated form with a pharmaceutically acceptable solvent such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated forms. The solvate contains a stoichiometric or non-stoichiometric amount of solvent and can be formed during crystallization with a pharmaceutically acceptable solvent such as water, ethanol or the like. The hydrate is formed when the solvent is water, or the alcoholate is formed when the solvent is an alcohol. Additionally, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

When the range of values is provided, it is understood that the respective upper and lower limits of the range and the intervening values between the upper and lower limits are included in the examples.

Instructions

Some embodiments disclosed herein are directed to a method of treating and/or ameliorating picornavirus infection, which can comprise administering to an individual infected with a picornavirus an effective amount of one or more compounds described herein (such as Formula (I) And/or (II) a compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein, such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof . Other embodiments disclosed herein are directed to a method of treating and/or ameliorating picornavirus infection, which can comprise administering to an individual identified as having a viral infection an effective amount of one or more of the compounds described herein (such as Formula (I) )and/ Or a compound of (II) or a pharmaceutically acceptable salt thereof) or a compound described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof).

Some embodiments described herein are directed to the use of one or more compounds described herein, such as a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in manufacturing And/or an agent for treating a picornavirus infection, the improvement and/or treatment comprising administering to the individual infected with the picornavirus an effective amount of one or more of the compounds described herein (such as Formula (I) and/or (II) a compound or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to one or more compounds described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof), which are useful for infection with picornavirus The individual is administered an effective amount of one or more of the compounds described herein to ameliorate and/or treat the picornavirus infection.

Some embodiments disclosed herein are directed to methods of ameliorating and/or treating picornavirus infections, which can include culturing a virus-infected cell with an effective amount of one or more compounds described herein (such as Formula (I) and/or ( a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described herein, such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof, is contacted . Other embodiments described herein are directed to the use of one or more compounds described herein, such as a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in manufacturing for improvement and/or Or treating an agent for picornavirus infection, the improvement and/or treatment can comprise contacting a cell infected with the picornavirus with an effective amount of the compound. Other embodiments described herein are those relating to one or more compounds described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof), which are useful for An effective amount of the (etc.) compound contacts to improve and/or treat the picornavirus infection.

Some embodiments disclosed herein are directed to methods of inhibiting picornavirus replication, which can comprise sensitizing a virus-infecting cell with an effective amount of one or more compounds described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof) or one or more A pharmaceutical composition of a compound described herein, such as a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof, is contacted. Other embodiments described herein are directed to the use of one or more compounds described herein, such as a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a small ribose A nucleic acid virus replicating agent, the inhibiting comprising contacting the virus-infected cell with an effective amount of the (etc.) compound. Other embodiments described herein are those relating to a compound described herein, such as a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, which can be used to administer a virus-infected cell Contact with an effective amount of the (etc.) compound to inhibit picornavirus replication. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, inhibits RNA-dependent ribonucleic acid polymerases of picornaviruses, and thus inhibits replication of RNA. In some embodiments, the picornavirus polymerase can be obtained by sensitizing a cell infected with a picornavirus to a compound described herein (such as a compound of formula (I) and/or (II) or a pharmaceutically acceptable compound thereof Salt) contact to suppress.

In some embodiments, the picornavirus can be selected from the group consisting of foot-and-mouth disease virus, enterovirus, rhinovirus, hepatic virus, and diarrhea virus. Among enteroviruses, there are several enterovirus types, including enterovirus A, enterovirus B, enterovirus C, enterovirus D, enterovirus E, enterovirus F, enterovirus G, enterovirus H, and enterovirus J. Each enterovirus type includes several serotypes. Examples of enterovirus serotypes include the following: poliovirus 1, poliovirus 2, poliovirus 3, echovirus 1, echovirus 2, echovirus 3, echovirus 4, Echovirus 5, Echovirus 6, Echovirus 7, Echovirus 9, Echovirus 11, Echovirus 12, Echovirus 13, Echovirus 14, Echovirus 15, Echovirus 16, Echovirus 17, Echovirus 18, Echovirus 19, Echovirus 20, Echovirus 21, Echovirus 24, Echovirus 25, Echovirus 26, Echovirus 27, Echovirus 29, Echovirus 30, Echovirus 31, Echovirus 32, Echovirus 33, Enterovirus 68, Enterovirus 69, Enterovirus 70, Enterovirus 71 and Vilnius human encephalomyelitis virus . In some embodiments, this article The compounds described, for example, a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt as described above, may ameliorate and/or treat enterovirus infection. For example, by administering to a subject infected with enterovirus an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof and/or a cell infected with enterovirus by contact. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) inhibits enterovirus replication. In some embodiments, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt as described above is effective against enterovirus, and thereby one or more symptoms of enterovirus infection are ameliorated. In some embodiments, the enterovirus can be enterovirus A. In other embodiments, the enterovirus can be enterovirus B. In other embodiments, the enterovirus can be enterovirus C. In other embodiments, the enterovirus can be enterovirus D. In other embodiments, the enterovirus can be enterovirus E. In other embodiments, the enterovirus can be enterovirus F. In other embodiments, the enterovirus can be enterovirus G. In other embodiments, the enterovirus can be enterovirus H. In other embodiments, the enterovirus can be enterovirus J.

The Coxsackie virus is divided into Group A and Group B. It was noted that group A kosaki virus caused flaccid paralysis, while group B tasaki virus was noted to cause spastic paralysis. Identification of 20 serotypes over group A (CV-A1, CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8, CV-A9, CV-A10 , CV-A11, CV-A12, CV-A13, CV-A14, CV-A15, CV-A16, CV-A17, CV-A18, CV-A19, CV-A20, CV-A21, CV-A22 and CV -A23) and six serotypes of group B (CV-B1, CV-B2, CV-B3, CV-B4, CV-B5 and CV-B6). Non-specific treatment for Coxsackie virus infection is currently approved. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) can ameliorate and/or treat a Coxsackie virus infection. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) inhibits coxsackievirus replication. In some embodiments, a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt as described above is effective against Coxsackie virus as demonstrated by an improvement in one or more symptoms of Coxsackie virus infection. In some embodiments, Coxsackie virus infection can be achieved by administering to a subject infected with a Coxsackie virus an effective amount of a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt as described above and/or a contact with a Coxsackie virus. Cells to improve, treat and/or inhibit. In some embodiments, the Coxsackie virus can be Coxsackievirus A. In other embodiments, the Coxsackie virus can be Coxsackievirus B. In some embodiments, the compounds described herein (one or more compounds of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof) may improve and/or treat coxsackie A virus-induced hands and foods And mouth disease.

Additional types of enteroviruses include rhinovirus A, rhinovirus B, and rhinovirus C. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) can ameliorate and/or treat a rhinovirus infection. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a salt of a pharmaceutically acceptable salt of the foregoing) inhibits rhinovirus replication. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) is effective against a variety of rhinovirus serotypes. For example, a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt as described above can be used to ameliorate and/or treat 2, 5, 10, 20, 40, 60, 80 or 80 or more rhinovirus serums. type. In some embodiments, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof described above is effective against a rhinovirus and thereby thereby ameliorating one or more symptoms of a rhinovirus infection. In some embodiments, a rhinovirus infection can be administered by administering to a subject infected with rhinovirus an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof and/or a contact with a rhinovirus. Cells to improve, treat and/or inhibit. In some embodiments, the Coxsackie virus can be Coxsackievirus A. In some embodiments, the rhinovirus can be rhinovirus A. In other embodiments, the rhinovirus can be rhinovirus B. In other embodiments, the rhinovirus can be rhinovirus C.

Another type of enterovirus is a liver virus. Hepatitis A is a hepatic serotype. Several human genotypes of hepatitis A are known, IA, IB, IIA, IIB, IIIA and IIIB. Genotype I is the most common. To date, there has been no treatment for hepatitis A infection with specific therapies. Specifically, treatment is essentially supportive. In some embodiments, the compounds described herein (eg, A compound of formula (I) and / or (II) or a pharmaceutically acceptable salt as described above may improve and/or treat a hepatic viral infection, such as a hepatitis A virus infection. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt as described above) inhibits replication of a hepatic virus (eg, Hepatitis A virus). In some embodiments, a compound of Formula (I) and/or (II) or a salt of the aforementioned TCM acceptable can treat and/or ameliorate hepatitis A genotype I. In some embodiments, the compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof is effective against more than one Type A hepatitis genotype, eg, 2, 3, 4, 5 or 6 Hepatitis A genes type. In some embodiments, a hepatic virus infection can be administered by administering to a subject infected with a hepatic virus an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof and/or a contact with an infected liver virus. Cells to improve, treat and/or inhibit.

Double echovirus is another type of enterovirus. Double Echovirus serotypes include human double Echovirus 1 (Echovirus 22), human double Echovirus 2 (Echovirus 23), human double Echovirus 3, human double Echovirus 4, human double angstrom It can be virus 5 and human double echovirus 6. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) may ameliorate and/or treat a dioxin virus infection. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) inhibits diarrhea virus replication. In some embodiments, the compound of Formula (I) and/or (II) or a previously acceptable salt of the above-described Chinese medicine is effective against more than one diarrhea virus serotype. In some embodiments, the EDV virus infection can be administered by administering to the individual infected with bisexavirus an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt and/or a combination thereof. Cells infected with double echovirus are improved, treated and/or inhibited.

Other genera of picornaviruses include the following: Aikmavirus, Avian Hepatitis, Cardiovirus, Kosovo, Desivirus, equinevirus, Spiral, M. genus, Sarivirus, Sapolovirus, Seneca, genus and tremor virus. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) may be ameliorated and/or treated selected from the group consisting of Virus-infected picornavirus infection: Aikma virus, avian liver virus, heart virus, Kosovo, diazepam, equine virus, genus, genus, genus Sarivirus, Sapolovirus, Seneca, genus and tremor virus. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) inhibits replication of a picornavirus selected from the group consisting of: Acquamavirus , avian hepatic genus, heart genus, coxial genus, diazepam, equine rhinovirus, genus genus, genus genus, sarivirus, sapolovirus, seneca Genus, Jieshen virus and tremor virus. A compound described herein (eg, a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) can be administered to an individual infected with the virus in an effective amount of a compound described herein and/or by Infecting a virus-infected cell with an effective amount of a compound described herein to ameliorate, treat, and/or inhibit a virus selected from the group consisting of: Acquamavirus, Avian Hepatitis, Cardiovirus, Coxvirus, Land Western virus, equine rhinovirus, genus genus, genus genus, sarivirus, saplovirus, seneca, genus and tremor.

In some embodiments, an effective amount of a compound of formula (I) and /(II) or a pharmaceutically acceptable salt thereof, or an effective amount of one or more compounds of formula (I) and / or (II) or a conventional Chinese medicine A pharmaceutical composition of an acceptable salt is effective for treating more than one genus of picornaviruses. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) can be used to ameliorate and/or treat more than one type of picornavirus. For example, a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt as described above can be used to ameliorate and/or treat 2, 3, 4, 5 or more types of enteroviruses. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) is effective to treat a plurality of serotypes of the picornaviruses described herein. For example, a compound described herein (one or more compounds of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof) is effective for treating 2, 5, 10, 15 or more Coxsacks Virus serotype.

Some embodiments disclosed herein are directed to a method of treating and/or ameliorating a Flaviviridae viral infection, which can comprise administering to an individual infected with Flaviviridae an effective amount of one or more compounds described herein (such as Formula (I) And/or (II) a compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof ). Other embodiments disclosed herein are directed to a method of treating and/or ameliorating a Flaviviridae viral infection, which can comprise administering to an individual an effective amount of one or more compounds described herein (such as Formula (I) and/or (II) a compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein, such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof. Some embodiments described herein are directed to the use of one or more compounds described herein, such as a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in manufacturing Or an agent for treating a Flaviviridae viral infection, the improvement and/or treatment comprising administering an effective amount of one or more of the compounds described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable compound thereof Accept the salt). Other embodiments described herein pertain to one or more compounds described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof), which are useful for administering an effective amount to an individual One or more of the compounds described herein to ameliorate and/or treat a Flaviviridae viral infection.

Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a Flaviviridae viral infection, which can include contacting a virus-infected cell with an effective amount of one or more compounds described herein (such as Formula (I) and/or ( II) a compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising one or more compounds described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof). Other embodiments described herein are directed to the use of one or more compounds described herein (eg, a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in manufacturing for improvement and/or Or an agent for treating a Flaviviridae viral infection, the improvement and/or treatment comprising contacting the virus-infected cell with an effective amount of the (etc.) compound. Other embodiments described herein pertain to one or more compounds described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof), which are useful for infecting a virus The cells are contacted with an effective amount of the (etc.) compound to improve and/or treat the Flaviviridae viral infection.

Some embodiments disclosed herein are directed to a method of inhibiting replication of a Flaviviridae virus, which can comprise incubating a virus-infected cell with an effective amount of one or more compounds described herein (such as a compound of Formula (I) and/or (II) or A pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising one or more compounds described herein, such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof, is contacted. Other embodiments described herein are directed to the use of one or more compounds described herein, such as a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a flavivirus The agent for replicating the virus, the inhibition comprising contacting the virus-infected cell with an effective amount of the compound. Other embodiments described herein are directed to a compound described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof) which is useful for efficacious cells The amount of the (etc.) compound is contacted to inhibit replication of the Flaviviridae virus. In some embodiments, a polymerase of a Flaviviridae virus can be obtained by reacting a cell infected with a Flaviviridae virus with a compound described herein (such as a compound of Formula (I) and/or (II) or a pharmaceutically acceptable compound thereof The salt) is contacted to inhibit, and thereby inhibiting the replication of the RNA.

HCV is a coated positive-stranded RNA virus in the Flaviviridae family. There are a variety of non-structural proteins of HCV, such as NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B. Xianxin NS5B is an RNA-dependent RNA polymerase involved in HCV RNA replication.

Some embodiments disclosed herein are directed to methods of ameliorating and/or treating an HCV infection, which can comprise subjecting a cell infected with HCV to an effective amount of one or more compounds described herein (such as a compound of formula (I) and / or (II) Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising one or more compounds described herein, such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof. Other embodiments described herein are directed to the use of one or more compounds described herein, such as a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, For use in the manufacture of an agent for ameliorating and/or treating an HCV infection, the improvement and/or treatment can comprise contacting a cell infected with HCV with an effective amount of the compound. Other embodiments described herein pertain to one or more compounds described herein (such as a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof), which are useful for cytotoxic cells Contact with an effective amount of the (etc.) compound to improve and/or treat HCV infection.

Some embodiments described herein are directed to a method of inhibiting NS5B polymerase activity, which can comprise culturing a cell infected with a hepatitis C virus with an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable compound thereof Accept the salt contact. Some embodiments described herein are directed to a method of inhibiting NS5B polymerase activity, which can comprise administering to a subject infected with a hepatitis C virus an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically thereof thereof. Acceptable salt. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, inhibits RNA-dependent ribonucleic acid polymerase, and thus inhibits replication of HCV RNA. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, inhibits HCV polymerase (eg, NS5B polymerase).

Some embodiments described herein are directed to a method of treating a condition selected from one or more of liver fibrosis, cirrhosis, and liver cancer selected from the aforementioned condition of a liver condition, which may comprise administering to the individual an effective condition A compound or pharmaceutical composition (e.g., a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) as described herein, wherein the liver condition is caused by HCV infection. Some embodiments described herein are directed to a method of increasing liver function in an individual having an HCV infection, which can comprise administering to the subject an effective amount of a compound or pharmaceutical composition described herein (eg, Formula (I) and / Or (II) a compound or a pharmaceutically acceptable salt thereof). Also contemplated is a method for reducing or eliminating liver damage caused by other viruses in an individual having an HCV infection by administering to the individual an effective amount of a compound or pharmaceutical composition described herein (eg, formula (I) And/or (II) a compound or a pharmaceutically acceptable salt thereof). In some embodiments, the method can include slowing or preventing progression of liver disease. In other embodiments, the disease process can be reversed and liver function is expected to be stable or improved. In some embodiments, Hepatic fibrosis can be treated by contacting a cell infected with hepatitis C virus with an effective amount of a compound described herein (e.g., a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt as described above). , liver cirrhosis and / or liver cancer; can improve liver function; can reduce or eliminate liver damage caused by the virus; can slow or halt the progress of liver disease; can reverse the liver disease process and / or can improve or maintain liver function.

There are multiple genotypes of HCV and multiple subtypes within each genotype. For example, eleven (numbered 1 to 11) major HCV genotypes are currently known, but others classify genotypes into six major genotypes. Each of these genotypes is further subdivided into subtypes (1a-1c; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a-7b; 8a-8b; 9a; 10a; 11a). In some embodiments, an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof, or an effective amount of a compound of formula (I) and / or (II) or a pharmaceutically acceptable pharmaceutical product as described above The pharmaceutical composition of the salt is effective for treating at least one HCV genotype. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof) is effective to treat all 11 HCV genotypes. In some embodiments, the compounds described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) are effective for treating three or more, five or more , 7 or more or 9 or more HCV genotypes. In some embodiments, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt as described above may be more effective against a greater number of HCV genotypes than the standard of care. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be more effective against a particular HCV genotype (such as genotypes 1, 2, 3, 4, 5, and / or 6).

A variety of indications for determining the utility of a method of treating HCV infection are known to those skilled in the art. Examples of suitable indications include, but are not limited to, reduced viral load, reduced viral replication, reduced time to seroconversion (undetectable virus in the patient's serum), increased rate of sustained viral response to therapy, and incidence in clinical outcomes Or reduced mortality, decreased liver function decline rate, stable liver function, improved liver function, one or more liver dysfunction markers (including alanine transaminase, aspartate transaminase, total bilirubin, bound bile red Inhibition of gamma, gamma glutamine thiol transpeptidase) and/or other disease responses. Similarly, successful treatment of an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof) reduces the incidence of liver cancer in an HCV infected individual .

In some embodiments, an effective amount of a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, is effective to reduce the HCV virus titer to an undetectable level (eg, to about 100 per milliliter of serum). To an amount of from about 500, from about 50 to about 100, from about 10 to about 50, or from about 15 to about 25 international units. In some embodiments, an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof is compared to a compound of formula (I) and/or (II) or a pharmaceutical thereof. The HCV viral load prior to the acceptable salt is effective to reduce the amount of HCV viral load. For example, wherein prior to administration of a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt as described above, and using a compound of formula (I) and / or (II) or its medicinal The HCV viral load is again measured after completion of the treatment regimen for the acceptable salt (eg, 1 month after completion). In some embodiments, an effective amount of a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be an amount effective to reduce the HCV viral load to less than about 25 international units per milliliter of serum. In some embodiments, an effective amount of a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, is an amount effective to achieve a reduction in HCV virus titer in an individual's serum, as compared to The viral load prior to administration of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof is from about 1.5 log to about 2.5 log reduction, from about 3 log to about 4 log reduction or more than about 5 log reduction Within the scope. For example, the HCV viral load can be measured prior to administration of a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof and upon completion of a compound of formula (I) and / or (II) or The measurement is again performed after the treatment of the pharmaceutically acceptable salt (for example, 1 month after completion).

In some embodiments, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can cause hepatitis C in an individual, as determined after completion of the treatment regimen (eg, one month after completion) Viral replication is reduced by at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 or more times relative to pre-treatment levels. In some embodiments, Formula (I) and Or a compound of (II) or a pharmaceutically acceptable salt thereof, which results in a reduction in the replication of hepatitis C virus relative to the pre-treatment level of from about 2 to about 5 times, from about 10 to about 20 times, from about 15 to about 40 times. Or in the range of about 50 to about 100 times. In some embodiments, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can result in a pegylated interferon and ribavirin administered in accordance with a standard of care. The combined reduction in hepatitis C virus reduction achieved in 1 to 1.5 logs, 1.5 logs to 2 logs, 2 logs to 2.5 logs, 2.5 to 3 logs, 3 logs to 3.5 logs, or 3.5 to 4 logs or more for hepatitis C virus replication Reduced replication of hepatitis C virus within a reduced range, or comparable to the reduction achieved after six months of standard therapy using ribavirin and pegylated interferon, in a shorter period of time (eg, one month, two Month or three months) achieve the same reduction as standard care for care.

In some embodiments, an effective amount of a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, is an amount effective to achieve a sustained viral response, such as HCV RNA in an individual's serum after treatment has ceased Undetectable or substantially undetectable (eg, less than about 500, less than about 200, less than about 100, less than about 25, or less than about 15 international units per milliliter of serum) for at least about one month, at least about two months, at least about A period of three months, at least about four months, at least about five months, or at least about six months.

In some embodiments, an effective amount of a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, provides a marker for liver fibrosis as compared to a marker in an untreated individual. Or a placebo-treated individual reduces at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%. At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more than 80%. Methods for measuring serum markers are known to those skilled in the art and include immunological methods using antibodies specific for a given serum marker, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and A similar method. A non-limiting list of examples of markers includes measuring serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma- glutamine using known methods. Transpeptide The content of enzyme (GGT) and total bilirubin (TBIL). In general, an ALT level of less than about 45 IU/L (International Units/Liter), an AST in the range of 10-34 IU/L, an ALP in the range of 44-147 IU/L, a GGT in the range of 0-51 IU/L, TBIL in the range of 0.3-1.9 mg/dL is considered normal. In some embodiments, an effective amount of a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be effective to reduce ALT, AST, ALP, GGT, and/or TBIL levels to be considered normal. The amount of the content of the content.

Individuals clinically diagnosed with HCV infection include "untreated" individuals (eg, individuals who have not previously been treated with HCV, especially those who have not previously received IFN-α and/or ribavirin-based therapies) and have been treated with previous HCV Individuals who fail ("treatment failure" individuals). Individuals who fail to treat include "non-responders" (ie, by previous HCV treatment (eg, previous IFN-α monotherapy, previous IFN-α and ribavirin combination therapy or previous pegylated IFN-α and ribavirin combination therapy) HCV titer is not significantly or sufficiently reduced ( 0.5 log IU/mL); and "relapsed" (ie, previously treated with HCV (eg, receiving prior IFN-α monotherapy, previous IFN-α and ribavirin combination therapy or previous PEGylated IFN-α) The HCV titer of individuals with ribavirin combination therapy is reduced and subsequently increased).

In some embodiments, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered to a subject who has failed treatment with HCV. In some embodiments, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered to a non-responder individual suffering from HCV. In some embodiments, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered to a relapsed individual suffering from HCV.

After a period of time, the infectious agent can develop resistance to one or more therapeutic agents. The term "drug resistance" as used herein refers to a viral strain exhibiting a delay, a decrease, and/or a non-reactivity to a therapeutic agent. For example, after treatment with an antiviral agent, the degree of reduction in viral load of an individual infected with a drug-resistant virus can be lower than the amount of viral load exhibited by an individual infected with a non-resistant virus strain. In some embodiments, an HCV strain that is resistant to infection with one or more different anti-HCV agents, such as those used in conventional care standards, can be administered. The individual is administered a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the individual is then treated with a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof to produce a drug-resistant HCV strain as compared to the production of other HCV drugs (such as conventional The agent used in the standard of care) is delayed in the resistant HCV strain.

In some embodiments, an effective amount of a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered to an individual who bans other anti-HCV agents. For example, pegylation of interferon is prohibited in individuals with hemoglobin (eg, thalassemia major, sickle cell anemia) and other individuals at risk of hematologic side effects of current therapies The combination of α and ribavirin is administered. In some embodiments, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, may be provided to an individual who is allergic to interferon and/or ribavirin.

Some HCV-treated individuals experience a viral load rebound. The term "virus load rebound" as used herein refers to the continuation of the viral load before the end of treatment. 0.5 log IU/mL increase, the lowest point being from baseline 0.5 log IU/mL was reduced. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered to an individual experiencing a viral load rebound, or can be prevented when used to treat an individual. Rebound.

The standard of care for the treatment of HCV is associated with several side effects (adverse events). In some embodiments, a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, is reduced in HCV patients treated with ribavirin and pegylated interferon according to a standard of care The number of side effects and/or the severity of side effects. Examples of side effects include, but are not limited to, fever, discomfort, tachycardia, chills, headache, joint pain, myalgia, fatigue, stagnation, loss of appetite, nausea, vomiting, cognitive changes, fatigue, narcolepsy, lack of positivity, Irritable, confused, depressed, severe depression, suicidal ideation, anemia, low white blood cell count and hair thinning. In some embodiments, one or more adverse effects or side effects associated with one or more other HCV agents, such as those used in conventional care standards, may be An individual who discontinues chronic hepatitis C virus therapy provides a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) may ameliorate and/or treat a Flavivirus infection. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) inhibits Flavivirus replication.

In some embodiments, the Flavivirus genus can be West Nile virus. West Nile infection can cause fever in the West Nile or severe West Nile disease (also known as West Nile encephalitis or meningitis or West Nile polio). Symptoms of West Nile fever include fever, headache, fatigue, body aches, nausea, vomiting, rash (body trunk), and swollen lymph glands. Symptoms of West Nile disease include headache, high fever, stiff neck, cramps, disorientation, coma, tremors, convulsions, muscle weakness, and paralysis. The current treatment for West Nile virus infection is supportive and currently no vaccination for humans.

In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) can treat and/or ameliorate dengue viruses, such as DENV-1, DENV-2 , DENV-3 and DENV-4. Dengue virus infection can cause hemorrhagic dengue fever and/or dengue shock syndrome. In some embodiments, a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) can treat and/or ameliorate hemorrhagic dengue and/or dengue shock syndrome. According to the World Health Organization (WHO), the global incidence of dengue fever has increased significantly in recent decades. To date, there has been no treatment for dengue virus infection. In addition, recovery from a dengue virus serotype infection provides only partial and temporary immunity against other serotypes. Subsequent infection with another serotype increases the likelihood of severe dengue (formerly known as hemorrhagic dengue). Hyperthermia (approximately 104°F) is suspected of being a dengue infection with one or more of the following symptoms: severe headache, post-ocular pain, muscle and joint pain, nausea, vomiting, glandular enlargement, and rash.

Yellow fever is an acute viral hemorrhagic disease. As provided by the WHO, up to 50% of untreated severely affected people die from yellow fever. It is estimated that there are 200,000 cases of yellow fever per year worldwide, resulting in 30,000 deaths. As with other flaviviruses, there is no cure or specific treatment for yellow fever, and treatment with ribavirin and interferon is inadequate. In some embodiments, the Flavivirus genus can be a yellow fever virus. Symptoms of yellow fever infection include fever, muscle pain with significant back pain, headache, tremors, loss of appetite, nausea, vomiting, jaundice, and bleeding (eg, from the mouth, nose, eyes, and/or stomach).

In other embodiments, the flavivirus may be an encephalitis virus in the genus Flavivirus. Examples of encephalitis viruses include, but are not limited to, Japanese encephalitis virus, St. Louis encephalitis virus, and arbovirus encephalitis. Encephalitis virus causes inflammation of the brain and/or meninges. Symptoms include high fever, headache, sensitivity to light, stiff neck and back, vomiting, confusion, epilepsy, paralysis, and coma. There are no specific treatments for encephalitis infections such as Japanese encephalitis, St. Louis encephalitis, and arbovirus encephalitis.

A variety of indications for determining the utility of methods of treating picornaviruses and/or Flaviviridae viral infections are known to those skilled in the art. Examples of suitable indications include, but are not limited to, reduced viral load, reduced viral replication, reduced time to seroconversion (undetectable virus in the patient's serum), decreased morbidity or mortality in clinical outcomes, and/or other disease response Instructions. Other indications include one or more overall quality of life health indicators, such as reduced duration of disease, reduced severity of the disease, reduced time to return to normal health and normal activities, and reduced time to relieve one or more symptoms. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can result in one or more of the foregoing indications being compared to an individual who is receiving a standard of care (for HCV) or not The treatment individual (small RNA virus and other Flaviviridae infections other than HCV) is relieved, alleviated or positively indicated. The role/symptoms of picornavirus infection are described herein and include, but are not limited to, fever, blisters, rash, meningitis, conjunctivitis, acute hemorrhagic conjunctivitis (AHC), sore throat, nasal congestion, runny nose, Sneezing, coughing, loss of appetite, muscle pain, headache, fatigue, nausea, jaundice, encephalitis, herpetic angina, myocarditis, pericarditis, meningitis, Bornholm disease, myalgia, nasal congestion, muscle weakness, loss of appetite, fever, vomiting, abdominal pain, abdominal discomfort, urinary redness and muscle pain. The role/symptoms of the Flaviviridae virus infection are also described herein.

In some embodiments, the length of time that the compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can cause one or more symptoms associated with picornavirus or Flaviviridae infection and/or Or severity is reduced compared to individuals receiving untreated standards (for HCV) or untreated individuals (small RNA and other Flaviviridae infections other than HCV). Table 1 provides the use of a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof and a standard of care (for HCV) or an untreated individual (small RNA and other flaviviruses other than HCV) Sectional infections) compare some of the examples of improved percentages obtained. Examples include the following: In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof results in a percentage of non-responders than a non-responder who receives a standard of care for chronic hepatitis C virus The percentage is 10% less; in some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof results in a disease duration that is experienced by an individual not treated for a yellow fever virus infection. The duration of the disease is from about 10% to about 30% lower; and in some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof causes symptom severity (such as described herein) One of the symptoms) is 25% less severe than the same symptom experienced by individuals not treated for dengue virus infection. Methods for quantifying the severity of side effects and/or symptoms are known to those skilled in the art.

In some embodiments, the compound can be a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof, wherein R ^1A is hydrogen. In other embodiments, the compound can be a compound of formula (I) and / or (II) wherein the compound of formula (I) and / or (II) is a monophosphate, diphosphate or triphosphate or pharmaceutically acceptable Acceptable salt. In other embodiments, the compound can be a compound of formula (I) and/or (II) wherein the compound of formula (I) and/or (II) is a thiomonophosphate, alpha-thiodiphosphate or alpha- Thiotriphosphate or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof, which may be used to ameliorate and/or treat picornavirus infection and/or inhibit picornavirus replication, may be Any of the embodiments provided in any of the embodiments described in paragraph A - paragraph B.

As used herein, "individual" refers to an animal that is the target of treatment, observation, or experimentation. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates such as fish, crustaceans, reptiles and especially mammals. "Mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates (such as monkeys, chimpanzees and baboons, and especially humans). In some embodiments, the individual is a human.

As used herein, the term "treating, treatment, therapeutic" or "Therapy" does not necessarily mean completely curing or eliminating a disease or condition. Any relief of any undesirable signs or symptoms of a disease or condition to any degree can be considered a treatment and/or therapy. In addition, treatment may include the effect of deteriorating the overall health or appearance of the patient.

The terms "therapeutically effective amount" and "effective amount" are used to indicate the amount of active compound or agent that causes a given biological or medical response. For example, an effective amount of a compound can be an amount required to prevent, alleviate or ameliorate the symptoms of the disease or prolong the survival of the individual being treated. This reaction can occur in tissues, systems, animals or humans and includes amelioration of the signs or symptoms of the disease being treated. In view of the disclosure provided herein, an effective amount of judgement is within the skill of the art. The effective amount of a compound disclosed herein as a dose will depend on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the particular animal in the study. The dosage can be tailored to achieve the desired effect, but will depend on factors such as weight, diet, co-agent, and other factors recognized by those skilled in the art.

As will be apparent to those skilled in the art, the in vivo dosage and specific mode of administration to be administered will depend on the age, weight, severity of the disease, the mammalian species being treated, the particular compound employed, and the use of such compounds. It varies for the specific use. Determination of the effective dosage level (i.e., the level of dosage necessary to achieve the desired result) can be accomplished by those skilled in the art using conventional methods (e.g., human clinical trials and in vitro studies).

The dosage varies widely depending on the desired effect and the indication for treatment. Alternatively, as understood by those skilled in the art, the dosage can be calculated based on the body surface area of the patient. Although the exact dose will be determined on a per-drug basis, in most cases, some general effects on the dose can be made. The daily dosing regimen for an adult patient can be, for example, an oral dose of 0.01 mg and 3000 mg of each active ingredient, preferably from 1 mg to 700 mg, such as from 5 to 200 mg. The dose can be a single dose or a series of two or more doses administered during one or more days depending on the individual's needs. In some embodiments, the administration of the compound is continued for a period of continuous therapy, such as for a week or more, or for months or years. In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof is compared to a standard of care The dosage of the drug can be administered at a lower frequency. In some embodiments, a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, can be administered once daily. For example, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered once daily to an individual suffering from an HCV infection. In some embodiments, the total time of treatment of a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof may be less than the total time of the treatment regimen of the standard of care.

Where the human dose of the compound has been determined for at least some of the conditions, the same dosage or a dose of from about 0.1% to 500%, more preferably from about 25% to 250% of the determined human dose may be used. When the human dose is not determined, such as in the case of newly developed pharmaceutical compositions, suitable human doses can be freely derived from ED ₅₀ or ID ₅₀ values as defined by the Institute for Toxicity Research and Efficacy in Animals or from in vitro or in vivo studies. Other appropriate values are inferred.

In the case of administration of a pharmaceutically acceptable salt, the dosage can be calculated as the free base form. As will be appreciated by those skilled in the art, in certain instances, it may be desirable to administer the compounds disclosed herein in an amount that exceeds or even exceeds the preferred dosage ranges described above for effective and aggressive treatment, particularly invasive. Sexual disease or infection.

The dosage and time interval can be adjusted individually to provide a plasma level of the active moiety sufficient to maintain a modulating effect or a minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. The dosage required to achieve MEC will depend on individual characteristics and the route of administration. However, HPLC analysis or bioanalysis can be used to determine plasma concentrations. The dose interval can also be determined using the MEC value. The composition should be administered using a regimen that maintains a plasma level above 10-90%, preferably 30-90% and optimally 50-90% of the duration of MEC. In the case of topical administration or selective absorption, the effective local concentration of the drug may be independent of plasma concentration.

It should be noted that the attending physician knows how and when to terminate, interrupt or regulate administration due to toxicity or organ dysfunction. Conversely, the attending physician is also known to adjust the treatment to a higher level when the clinical response is inadequate (excluding toxicity). Dosing dose when treating the condition of interest The amount will vary depending on the severity of the condition to be treated and the route of administration. The severity of the condition can be assessed, for example, in part by standard prognostic assessment methods. In addition, the dose and possible dose frequency will vary depending on the age, weight and response of the individual patient. A program similar to the one described above can be used in veterinary medicine.

The efficacy and toxicity of the compounds disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a small class of compounds that share a certain chemical moiety can be determined by measuring the in vitro toxicity of a cell line, such as a mammalian and preferably a human cell line. The results of such studies are generally predictive of toxicity in animals, such as mammals or, more specifically, humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit or monkey, can be determined using known methods. The efficacy of a particular compound can be determined using a number of accepted methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, those skilled in the art can select appropriate models, dosages, routes of administration, and/or protocols from current state of the art guidance.

As described herein, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can have a moiety that neutralizes the charge of the phosphate or thiophosphate. By neutralizing the charge on the phosphate or thiophosphate, cell membrane penetration can be promoted due to increased lipophilicity of the compound. Once absorbed and employed within the cell, the group attached to the phosphate is readily removed by esterase, protease, and/or other enzymes. In some embodiments, the group attached to the phosphorus can be removed by simple hydrolysis. In the cell, the phosphate released can then be metabolized to a diphosphate or active triphosphate by cellular enzymes. Likewise, phosphorothioates can be metabolized to alpha-thiodiphosphate or alpha-thiotriphosphate. Furthermore, in some embodiments, altering the substituents on a compound described herein, such as a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof, can help to reduce undesirable effects ( Such as isomerization) to maintain the efficacy of such compounds.

In some embodiments, phosphorylation of a thiomonophosphate of a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be stereoselective. For example, a thiomonophosphate of a compound of formula (I) and/or (II) can be phosphorylated to obtain a (R) or (S) diastereomer with respect to the 5'-O-phosphorus atom. Concentrated alpha-thiodiphosphate and/or alpha-thiotriphosphate compound. For example, the 5'-O-phosphorus atom of the α-thiodiphosphate and/or α-thiotriphosphate compound is one of the (R) and (S) configurations and may be related to 5' -O-phosphorus atom is the other of the (R) or (S) configuration compared to >50%, 75%, 90%, 95% or 99% of the amount exists. In some embodiments, phosphorylation of a pharmaceutically acceptable salt of a compound of formula (I) and/or (II) can result in the formation of a compound having the (R) configuration at the 5'-O-phosphorus atom. In some embodiments, phosphorylation of a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can result in the formation of a compound having a (S) configuration at the 5'-O-phosphorus atom.

In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be used as a chain terminator for RNA synthesis. For example, a compound of formula (I) and/or (II) may contain a moiety at the 2'-carbon position such that once the compound is incorporated into the RNA strand, no further elongation is observed. For example, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, may contain a non-hydrogen 2'-carbon modification, such as optionally substituted _C1-6 alkyl, as appropriate Substituted C _2-6 alkenyl or optionally substituted C _2-6 alkynyl.

In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can have increased metabolism and/or plasma stability. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, may be more resistant to hydrolysis and/or more resistant to enzymatic conversion. For example, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof is the same as the structure but O ¹ is OH, and each of R ^A , R ^2A , R ^5A , R ^a1 and R ^a2 A compound which is hydrogen and each of R ^3A and R ^4A is OH may have improved metabolic stability, improved plasma stability, may be more resistant to hydrolysis and/or may be more resistant to enzymatic conversion. In some embodiments, a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, may have improved properties. A non-limiting list of exemplary properties includes, but is not limited to, prolonged biological half-life, increased bioavailability, increased potency, sustained in vivo response, increased dosing interval, reduced dosing, reduced cytotoxicity, and treatment of disease conditions. Reduced demand, reduced viral load, reduced time to seroconversion (ie, the virus becomes undetectable in the patient's serum), increased viral response, reduced morbidity or mortality in clinical outcomes, increased individual compliance, Hepatic conditions such as liver fibrosis, cirrhosis and/or liver cancer are alleviated and compatible with other agents. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can have a biological half life of greater than 24 hours. In some embodiments, the biological half-life of the compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof may be the same as the structure but O ¹ is OH, R ^A , R ^2A , R ^5A , R ^a1 and The compound in which each of R ^a2 is hydrogen and R ^3A and R ^4A are each OH is long. In some embodiments, the antiviral activity of the compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof is the same as the structure but O ¹ is OH, R ^A , R ^2A , R ^5A , A compound in which each of R ^a1 and R ^a2 is hydrogen and R ^3A and R ^4A are each OH is effective.

Further, in some embodiments, the presence of a portion that neutralizes the charge of the phosphate or thiophosphate can increase the stability of the compound by inhibiting decomposition of the compound. Moreover, in some embodiments, the presence of a portion that neutralizes the phosphate or thiophosphate charge can render the compound more resistant to decomposition in vivo and provide a prolonged prolonged effect. In some embodiments, the portion that neutralizes the phosphate or thiophosphate charge can facilitate penetration of the compound into the cell membrane by making the compound of Formula (I) and/or (II) more lipophilic. In some embodiments, neutralizing the phosphate or thiophosphate charge portion can have improved oral bioavailability, improved aqueous solution stability, and/or reduced risk of by-product related toxicity. In some embodiments, for comparison purposes, the compound of formula (I) and/or (II) may be the same structure but O ¹ is OH, and each of R ^A , R ^2A , R ^5A , R ^{a1 ,} and R ^a2 is hydrogen and ^A comparison of the compounds in which R ^3A and R ^4A are each OH.

Combination therapy

In some embodiments, a compound disclosed herein (such as a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof) or a compound described herein or a pharmaceutically acceptable salt thereof The pharmaceutical composition can be used in combination with one or more additional agents to treat, ameliorate and/or inhibit picornavirus and/or Flaviviridae infection.

In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered in a single pharmaceutical composition with one or more additional agents. In some embodiments The compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof may be administered as one or more additional pharmaceutical agents as two or more separate pharmaceutical compositions. For example, a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, can be administered in a pharmaceutical composition, and at least one of the additional agents can be in the second pharmaceutical composition. Cast. If at least two other agents are present, one or more of the additional agents may be in a first pharmaceutical composition comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof, and At least one of the additional agents can be in the second pharmaceutical composition.

Use of a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof, and The amount of administration and the time course of administration of a plurality of additional agents are within the knowledge of those skilled in the art. For example, when performing a conventional care therapy standard using a recognized dosing amount and dosing schedule, an effective amount and dosing regimen as described herein can be used in addition to or in lieu of one of the combination therapies. And a pharmaceutical composition of the compound of the formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a compound of the formula (I) and / or (II) or a pharmaceutically acceptable salt thereof.

The order of administration of the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof with one or more additional agents may vary. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered prior to all additional agents. In other embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered prior to at least one additional agent. In other embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional pharmaceutical agents. In other embodiments, a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, can be administered after administration of at least one additional agent. In some embodiments, a compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, can be administered after administration of all additional agents.

In some embodiments, a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents can result in additive effects. In some embodiments, a compound of formula (I) and/or (II), or a pharmaceutically acceptable compound thereof, for use in combination with one or more additional agents The combination of salts can lead to synergy. In some embodiments, a combination of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof for use in combination with one or more additional agents can result in a strong synergistic effect. In some embodiments, the combination of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof in combination with one or more additional agents is not antagonistic.

As used herein, the term "antagonistic" means that the activity of the combination of compounds is less than the sum of the activities of the compounds obtained when the activity of each compound is determined individually (i.e., in the form of a single compound). As used herein, the term "synergistic" means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds obtained when the activity of each compound is determined individually. As used herein, the term "additional" means that the activity of the combination of compounds is approximately equal to the sum of the individual activities of the compounds obtained when the activity of each compound is determined individually.

The potential advantage of using a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof in combination with one or more additional agents may be compared to when a compound of formula (I) and/or (II) is absent The amount required to achieve the same therapeutic result when one or more additional agents are administered, or a pharmaceutically acceptable salt thereof, reduces the effective treatment of the disease conditions disclosed herein (eg, picornavirus and/or flavivirus) Viral infection) The required amount of one or more additional agents. For example, for the treatment of HCV, compared to the amount of the compound of Figures 1-9 (including its pharmaceutically acceptable salts) required to achieve the same reduction in viral load when administered in a monotherapy form, The amount of the compound of 1-9, including its pharmaceutically acceptable salt, may be small. Another potential advantage of using a combination of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof with one or more additional agents is the use of two or more compounds having different mechanisms of action. Drug-resistant virus strains are organized to form higher barriers than barriers when compounds are administered by monotherapy.

Additional advantages of using a combination of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof with one or more additional agents may include a compound of formula (I) and / or (II) or a pharmaceutically acceptable Very little cross-resistance between acceptable salt and one or more of its additional agents to almost no cross-resistance A different elimination route of a compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof and one or more additional agents; a compound of the formula (I) and / or (II) or a pharmaceutically acceptable compound thereof Very little or no overlapping toxicity between the salt received and one or more additional agents; very little to almost no significant effect on cytochrome P450; a compound of formula (I) and / or (II) or a pharmaceutically acceptable compound thereof There is little to no pharmacokinetic interaction between the salt and one or more additional agents; compared to the percentage of individuals who achieve a sustained viral response when administering the compound as a monotherapy and/or a therapeutic time to achieve a sustained viral response Reduced when administered as a monotherapy.

For the treatment of picornavirus and/or flavivirus infection rather than HCV, a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or comprising formula (I) and / or (including Examples of additional agents for use in combination with a pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof include, but are not limited to, ribavirin and interferon (including those described herein).

For the treatment of HCV, a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof Examples of additional agents used in combination with the compositions include, but are not limited to, agents used in conventional care standards for the treatment of HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, other antiviral compounds, a compound of formula (AA) (including a pharmaceutically acceptable salt and a pharmaceutical composition which may comprise a compound of formula (AA) or a pharmaceutically acceptable salt thereof), a compound of formula (BB) (including pharmaceutically acceptable Salts and pharmaceutical compositions which may comprise a compound of formula (BB) or a pharmaceutically acceptable salt thereof, a compound of formula (CC), including pharmaceutically acceptable salts, and may include a compound of formula (CC) or a pharmaceutical thereof A pharmaceutical composition of an acceptable salt) and/or combinations thereof. In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The compositions can be used with one, two, three or more of the additional agents described herein. Combination of a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof A non-limiting list of examples is provided in Tables A, B, C, D, and E.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition can be used in combination with the agents currently used in the standard of conventional care therapy. For example, for the treatment of HCV, the compounds disclosed herein can be combined with pegylated interferon-α-2a (trade name PEGASYS®) and ribavirin, pegylated interferon-α-2b (trade name PEG-INTRON) ®) and ribavirin, pegylated interferon-α-2a, pegylated interferon-α-2b or ribavirin in combination.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition can replace the agents currently used in the standard of conventional care therapy. For example, for the treatment of HCV, a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a compound of formula (I) and / or (II) or a pharmaceutically acceptable compound thereof may be used. The pharmaceutical composition of the salt replaces ribavirin.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition can be used in combination with an interferon such as pegylated interferon. Examples of suitable interferons include, but are not limited to, pegylated interferon-α-2a (trade name PEGASYS®), pegylated interferon-α-2b (trade name PEG-INTRON®), and interferon (interferon alfacon-1) (trade name INFERGEN®), pegylated interferon lambda and/or combinations thereof.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition can be used in combination with an HCV protease inhibitor. A non-limiting list of exemplary HCV protease inhibitors includes the following: VX-950 (TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS-650032, SCH 503034 (BOCEPREVIR®), GS -9256, GS-9451, IDX-320, ACH-1625, ACH-2684, TMC-435, ITMN-191 (DANOPREVIR®) and / or a combination thereof. Suitable for combination with a pharmaceutical composition of the compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof or a compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof Additional HCV protease inhibitors include VP-19744, PSI-879, VCH-759/VX-759, HCV-371, IDX-375, GL-60667, JTK-109, PSI-6130, R1479, R-1626, R -7182, MK-0608, INX-8014, INX-8018, A-848837, A-837093, BILB-1941, VCH-916, VCH-716, GSK-71185, GSK-625433, XTL-2125 and PCT Publications As disclosed in WO 2012/142085, the case is hereby incorporated by reference for the purpose of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the present disclosure. A non-limiting list of exemplary HCV protease inhibitors includes the compounds numbered 1001-1016 in Figure 1.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition can be used in combination with an HCV polymerase inhibitor. In some embodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor. In other embodiments, the HCV polymerase inhibitor can be a non-nucleoside inhibitor. Examples of suitable nucleoside inhibitors include, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-189, PSI-352938, PSI-661, 4'-azidouridine (including 4'-azideuria) Known prodrugs of glycosides, GS-6620, IDX-184 and TMC649128 and/or combinations thereof. A non-limiting list of exemplary nucleoside inhibitors includes the compounds numbered 2001-2012 in Figure 2. Examples of suitable non-nucleoside inhibitors include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497, and/or Or a combination thereof. A non-limiting list of exemplary non-nucleoside inhibitors includes the compound numbered 3001-3014 in Figure 3. Suitable for combination with a pharmaceutical composition of the compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof or a compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof Other HCV polymerase inhibitors include VX-500, VX-813, VBY-376, TMC-435350, EZ-058, EZ-063, GS-9132, ACH-1095, The disclosures of IDX-136, IDX-316, ITMN-8356, ITMN-8347, ITMN-8096, ITMN-7587, VX-985, and PCT Publication No. WO 2012/142085.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition can be used in combination with an NS5A inhibitor. Examples of NS5A inhibitors include BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393, and/or combinations thereof. A non-limiting list of exemplary NS5A inhibitors includes the compound numbered 4001-4012 in Figure 4. Suitable for combination with a pharmaceutical composition of the compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof or a compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof Additional NS5A inhibitors include those disclosed in A-832, PPI-1301, and PCT Publication No. WO 2012/142085.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition can be used in combination with other antiviral compounds. Examples of other antiviral compounds include, but are not limited to, Debio-025, MIR-122 inhibitors (eg, Miravirsen (SPC3649)), cyclosporin A, and/or combinations thereof. A non-limiting list of exemplary other antiviral compounds includes the compound numbered 5001-5011 in Figure 5.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition may be combined with a compound of the formula (AA) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of the formula (AA) or a pharmaceutically acceptable salt thereof (see US publication filed on Dec. 20, 2012) Case No. 2013/0164261 A1, the contents of which are incorporated herein by reference in their entirety in their entirety in

Wherein: B ^AA1 is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having a protected amine group; R ^AA1 may be selected from O ^- , OH, optionally substituted N-bonded amine a base acid and optionally a substituted N-linked amino acid ester derivative; R ^AA2 may be absent or selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted Ring base and Wherein R ^AA6 , R ^AA7 and R ^AA8 may be independently absent or hydrogen, and n ^AA may be 0 or 1; the restriction is that when R ^AA1 is O ^- or OH, then R ^AA2 is absent and is hydrogen or ; R ^AA3 may be selected from the group ^{consisting of} hydrogen, halogen, -OR ^AA9 and -OC(=O)R ^AA10 ; R ^AA4 may be selected from halogen, -OR ^AA11 and -OC(=O)R ^AA12 ; or R ^AA3 and R ^AA4 All of which are oxygen atoms bonded via a carbonyl group; R ^AA5 may be selected from optionally substituted C _2-6 alkyl groups, optionally substituted C _2-6 alkenyl groups, optionally substituted C _2-6 Alkynyl and optionally substituted C _3-6 cycloalkyl; or R ^AA4 and R ^AA5 together form -(C _1-6 alkyl)-O- or -O-(C _1-6 alkyl)- ; R ^AA9 and R ^AA11 is independently hydrogen or optionally substituted alkyl group of C _1-6; and R ^AA10 and R ^AA12 may independently be optionally substituted by the C _1-6 alkyl or optionally substituted C _3-6 cycloalkyl. A non-limiting list of examples of compounds of formula (AA) includes the compound numbered 7000-7027 in Figure 7.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition may be combined with a compound of the formula (BB) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of the formula (BB) or a pharmaceutically acceptable salt thereof (see US publication as of June 28, 2012) Case No. 2012/0165286, the contents of which are hereby incorporated by reference in its entirety, in

Wherein B ^BB1 is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having a protected amine group; X ^BB may be O (oxygen) or S (sulfur); and R ^BB1 may be selected from - Z ^BB -R ^BB9 , optionally substituted N-linked amino acid and optionally substituted N-bonded amino acid ester derivative; Z ^BB may be selected from O (oxygen), S (sulfur) and N ( R ^BB10 ); R ^BB2 and R ^BB3 may be independently selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkyne a substituted C _1-6 haloalkyl group and optionally a substituted aryl group (C _1-6 alkyl group); or R ^BB2 and R ^BB3 may be bonded together to form a group selected from the group consisting of: a substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted C _3-6 aryl, and optionally substituted C _3-6 heteroaryl; R ^BB4 may be selected from the group consisting of hydrogen, halogen, azido, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkyne And optionally substituted alkenyl; R ^BB5 may be hydrogen or optionally substituted C _1-6 alkyl; R ^BB6 may be selected from hydrogen, Halogen, azido, amine, cyano, optionally substituted C _1-6 alkyl, -OR ^BB11 and -OC(=O)R ^BB12 ; R ^BB7 may be selected from hydrogen, halogen, azide, Cyano, optionally substituted C _1-6 alkyl, -OR ^BB13 and -OC(=O)R ^BB14 ; R ^BB8 may be selected from hydrogen, halogen, azide, cyano, optionally substituted C _1-6 alkyl, -OR ^BB15 and -OC(=O)R ^BB16 ; R ^BB9 may be selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally. Substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryl ( C _1-6 alkyl), optionally substituted heteroaryl (C _1-6 alkyl) and optionally substituted heterocyclic (C _1-6 alkyl); R ^BB10 may be selected from hydrogen, Substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally a substituted heteroaryl group, optionally substituted heterocyclic group The optionally substituted aryl (C _1-6 alkyl), optionally substituted aryl of heteroaryl (C _1-6 alkyl) and optionally substituted heterocyclyl group of the (C _1-6 alkyl); R ^BB11 , R ^BB13 and R ^BB15 may independently be hydrogen or optionally substituted C _1-6 alkyl; and R ^BB12 , R ^BB14 and R ^BB16 may independently be optionally substituted C _1-6 alkyl Or optionally substituted C _3-6 cycloalkyl. In some embodiments, at least one of R ^BB2 and R ^BB3 is not hydrogen. A non-limiting list of exemplary formula (BB) compounds includes the compound numbered 8000-8016 in Figure 8.

In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof or a medicament comprising a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof The composition may be combined with a compound of the formula (CC) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of the formula (CC) or a pharmaceutically acceptable salt thereof (see US disclosure filed on March 22, 2012) Case No. 2012/0071434, the contents of which are hereby incorporated by reference in its entirety, in

Wherein B ^CC1 is optionally substituted heterocyclic base or optionally substituted heterocyclic base having a protected amine group; R ^CC1 may be selected from O ^- , OH, optionally substituted N-bonded amine group An acid and optionally substituted N-linked amino acid ester derivative; R ^CC2 may be absent or selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic ring Base and Wherein R ^CC19, R ^CC20 and R ^CC21 independently absent or hydrogen, and n ^CC may be 0 or 1; with the proviso that when R ^CC1 is O ^- when or OH, then R ^CC2 is ; R ^CC3a and R ^CC3b may be independently selected from hydrogen, deuterium, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl; , optionally substituted C _1-6 haloalkyl and aryl (C _1-6 alkyl); or R ^CC3a and R ^CC3b may be bonded together to form an optionally substituted C _3-6 cycloalkyl; ^CC4 may be selected from hydrogen, azide, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; R ^CC5 optional From hydrogen, halogen, azido, cyano, optionally substituted C _1-6 alkyl, -OR ^CC10 and -OC(=O)R ^CC11 ; R ^CC6 may be selected from hydrogen, halogen, azide, Cyano, optionally substituted C _1-6 alkyl, -OR ^CC12 and -OC(=O)R ^CC13 ; R ^CC7 may be selected from hydrogen, halogen, azide, cyano, optionally substituted C ₆ alkyl, -OR ^CC14 and -OC (= O) R ^CC15; or R ^CC6 and R ^CC7 are both available from carbonyl oxygen atom and bonded together; R ^CC8 selected from hydrogen, halo, azido , cyano, the optionally substituted C _1-6 alkyl, -OR ^CC16 and ^{-OC (= O) R CC17;} R CC9 selected from hydrogen, azido, cyano, optionally substituted with Instead C _1-6 alkyl and ^{-OR CC18; R CC10, R CC12} , R CC14, R CC16 and R ^CC18 may be independently selected from hydrogen and optionally substituted alkyl group of C _1-6; and R ^CC11, R ^CC13 , R ^CC15 and R ^CC17 may be independently selected from optionally substituted C _1-6 alkyl and optionally substituted C _3-6 cycloalkyl. In some embodiments, when ^{R CC3a, R CC3b, R CC4} , R CC5, R CC7, R CC8 are both hydrogen, and R ^CC9 is not R ^CC6 is azido. In some embodiments, when R ^CC3a is hydrogen, R ^CC3b is hydrogen, R ^CC4 is H, R ^CC5 is OH or H, R ^CC6 is hydrogen, OH or -OC(=O)CH ₃ , and R ^CC7 is hydrogen, OH, OCH ₃ or -OC(=O)CH ₃ , R ^CC8 is hydrogen, OH or OCH ₃ , R ^CC9 is H and B ^CC1 is optionally substituted adenine, optionally substituted guanine, as appropriate R ^CC2 may not be substituted by substituted uracil or sub-xanthine as appropriate . In some embodiments, R ^{CC2 is} not . A non-limiting list of examples of compounds of formula (CC) includes the compound numbered 6000-6078 in Figure 6.

Some embodiments described herein are directed to a method of ameliorating or treating a picornavirus and/or Flaviviridae viral infection, which can comprise cultivating a virus-infected cell with an effective amount of Formula (I) and/or (II) The compound or a pharmaceutically acceptable salt thereof is contacted with a combination of one or more agents selected from the group consisting of interferon, ribavirin, a compound of formula (AA), a compound of formula (BB) and a compound of formula (CC) or a compound of the foregoing A pharmaceutically acceptable salt of either. Some embodiments described herein are directed to a method of ameliorating or treating an HCV infection, which can comprise administering an HCV-infected cell with an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable compound thereof. The salt is contacted with a combination of one or more agents selected from the group consisting of interferons, ribavirins, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, antiviral compounds, compounds of formula (AA), compounds of formula (BB) And a pharmaceutically acceptable salt of the compound of the formula (CC) or any of the foregoing compounds.

Some embodiments described herein are directed to a method of ameliorating or treating a picornavirus and/or Flaviviridae viral infection, which can comprise administering an effective amount of Formula (I) and/or ( II) a compound or a pharmaceutically acceptable salt thereof in combination with one or more agents selected from the group consisting of interferon, ribavirin, a compound of formula (AA), a compound of formula (BB) and a compound of formula (CC) or a compound of the foregoing A pharmaceutically acceptable salt of either of them. Some embodiments described herein are directed to a method of ameliorating or treating an HCV infection, which can comprise administering to a subject afflicted with an HCV infection an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable compound thereof a salt thereof in combination with one or more agents selected from the group consisting of interferons, ribavirins, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, antiviral compounds, compounds of formula (AA), compounds of formula (BB) And a pharmaceutically acceptable salt of the compound of the formula (CC) or any of the foregoing compounds.

Some embodiments described herein are directed to a method of inhibiting replication of a picornavirus and/or Flaviviridae virus, which may comprise incubating a virus-infected cell with an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof in contact with a combination of one or more agents selected from the group consisting of interferon, ribavirin, a compound of formula (AA), a compound of formula (BB) and a compound of formula (CC) or a compound of the foregoing Pharmaceutically acceptable salts. Some embodiments described herein are directed to a method of inhibiting replication of hepatitis C virus, which can comprise culturing a cell infected with HCV hepatitis virus with an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically acceptable compound thereof The salt received is contacted with a combination of one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (AA), formula (BB) And a pharmaceutically acceptable salt of the compound and the compound of the formula (CC) or any of the foregoing compounds.

Some embodiments described herein are directed to a method of inhibiting replication of a picornavirus and/or Flaviviridae virus, which can comprise administering to a subject infected with the virus an effective amount of a compound of formula (I) and/or (II). Or a combination of a pharmaceutically acceptable salt thereof and one or more agents selected from the group consisting of interferon, ribavirin, a compound of formula (AA), a compound of formula (BB) and a compound of formula (CC) or a compound of the foregoing Pharmaceutically acceptable salts. Some embodiments described herein are directed to a method of inhibiting replication of hepatitis C virus, which can comprise administering to a subject infected with HCV hepatitis virus an effective amount of a compound of formula (I) and/or (II) or a pharmaceutically thereof thereof. Combination of an acceptable salt with one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (AA), formula (BB) And a pharmaceutically acceptable salt of the compound and the compound of the formula (CC) or any of the foregoing compounds.

A non-limiting list of exemplary combinations of a pharmaceutical composition of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, and one or more additional agents is provided in the table A, B, C, D and E. The numbers X and Y compounds of Tables A, B, C, D and E have corresponding names and/or structures provided in Figures 1-9. The compounds of the numbers in Tables A, B, C, D and E include pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof. For example, 1001 includes a compound corresponding to 1001, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising Compound 1001 and/or a pharmaceutically acceptable salt thereof. The combinations exemplified in Tables A, B, C, D, and E are indicated by Formula X: Y, which represents the combination of Compound X and Compound Y. For example, the combination indicated as 1001:9044 in Table A indicates Compound 1001 and Compound 9044, including pharmaceutically acceptable salts of Compounds 1001 and/or 9044, and pharmaceutical compositions including Compounds 1001 and 9044 (including compounds) A combination of 1001 and/or a pharmaceutical composition of a pharmaceutically acceptable salt of Compound 9044). Thus, the combination indicated as 1001:9044 in Table A indicates Telaprevir (compound 1001, as shown in Figure 1) and (Compound 9044, as shown in Figure 9), comprising a pharmaceutically acceptable salt of Compound 1001 and/or 9044, and a pharmaceutical composition comprising Compounds 1001 and 9044 (including a medicament comprising Compound 1001 and/or Compound 9044) A combination of a pharmaceutical composition of a salt that is acceptable in the art. Each of the combinations provided in Tables A, B, C, D, and E can be used with one, two, three, or more of the additional agents described herein. In some embodiments described herein, the combination of agents can be used to treat, ameliorate and/or inhibit viral and/or viral infections, wherein the virus can be a picornavirus and/or a Flaviviridae virus and the viral infection can be a small ribose sugar. Nucleic acid virus infection and/or flavivirus.

Compound

Some embodiments disclosed herein relate to methods and/or uses of a compound of formula (I) or a pharmaceutically acceptable salt thereof: (paragraph A)

Wherein: B ^1A is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having a protected amine group; -------- may be absent or a single bond, the limitation is Two -------- neither exist or two -------- are single keys; when -------- are not present, then Z ¹ may not exist, O ¹ may be OR ^1A , R ^3A may be selected from H, halo, OH, -OC(=O)R" ^A and optionally substituted O-linked amino acid, and R ^4A may be selected from H, OH, halogen. a group, N ₃ , —OC(=O)R" ^B , optionally substituted O-linked amino acid, and NR" ^B1 R" ^B2 , or R ^3A and R ^4A may form a 5-membered ring via a carbonyl linkage. Oxygen atom; when --- each is a single bond, then Z ¹ can be , O ¹ may be O, R ^3A may be O; R ^4A may be selected from H, OH, halo, N ₃ , -OC(=O)R" ^B , optionally substituted O-linked amino acid and NR" ^B1 R"^B2; and R ^1B may be selected from O ^- , OH, -O-, optionally substituted by C _1-6 alkyl, , , , And optionally substituted N-linked amino acids and optionally substituted N-linked amino acid ester derivatives; R ^a1 and R ^a2 may independently be hydrogen or deuterium; R ^A may be hydrogen, deuterium or not Substituted C _1-3 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-3 alkynyl or cyano; R ^1A may be selected from hydrogen, optionally substituted thiol, O-linked amino acid, as appropriate, , and ; R ^2A may be hydrogen, halo, unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, -CHF ₂ , -(CH ₂ ) _1-6 halogen, -(CH ₂ ) _1-6 N ₃ , -(CH ₂ ) _1-6 NH ₂ or -CN; R ^5A may be selected from H, halo, OH, optionally substituted C _{a 1-6} alkyl group, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; R ^6A , R ^7A and R ^8A may be independently selected from the absence, hydrogen, optionally Substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl (C _1-6 alkyl), optionally substituted *- (CR ^15A R ^16A ) _p -OC _1-24 alkyl, optionally substituted *-(CR ^17A R ^18A ) _q -OC _1-24 alkenyl, , , ; or R ^6A can be And R ^7A may be absent or hydrogen; or R ^6A and R ^7A may be combined to form a moiety selected from the group consisting of: And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6A and R ^7A form a six to ten member ring system; R ^9A can be independently selected from optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, NR ^30A R ^31A , a substituted N-linked amino acid and optionally an N-bonded amino acid ester derivative; R ^10A and R ^11A may independently be an optionally substituted N-linked amino acid and optionally a substituted N-linked amino acid ester derivative; R ^12A and R ^13A may be independently absent or hydrogen; R ^14A may be O-, OH or methyl; each R ^15A , each R ^16A , each R ^17A and Each R ^18A may independently be hydrogen, optionally substituted C _1-24 alkyl or alkoxy; R ^19A , R ^20A , R ^22A , R ^23A , R ^2B , R ^3B , R ^5B and R ^6B may be independently Is selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^21A and R ^4B may be independently selected from hydrogen, optionally substituted C _1-24 alkyl, optionally where the substituted aryl, the optionally substituted -OC _1-24 alkyl, Where the substituted aryl group -O-, optionally substituted aryl group and the -O- heteroaryl optionally substituted monocyclic heterocyclic group of -O-; R ^24A and R ^7B are independently selected from hydrogen, optionally Substituted C _1-24 alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O- a heteroaryl group, optionally substituted -O-monocyclic heterocyclic group and ; R ^25A , R ^26A , R ^29A , R ^8B and R ^9B may be independently selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^27A1 and R ^27A2 may independently Selected as -C≡N, optionally substituted C _2-8 organic carbonyl, optionally substituted C _2-8 alkoxycarbonyl, and optionally substituted C _{2-8organidoaminocarbonyl} ; R ^28A It may be selected from hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 Cycloalkyl and optionally substituted C _3-6 cycloalkenyl; R ^30A and R ^31A are independently selected from hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 Alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, and optionally substituted aryl (C _1-4 alkyl); R" ^A and each R" ^B may independently be optionally substituted C _1-24 alkyl; each R" ^B1 and each R" ^B2 may independently be hydrogen or optionally substituted C _1-6 alkyl; m, v and w may independently be 0 or 1; p and q may independently be 1, 2 or 3; r and s may independently 0, 1, 2 or 3; t may be 1 or 2; u and y may independently be 3, 4 or 5; and Z ^1A , Z ^2A , Z ^3A , Z ^4A , Z ^1B and Z ^2B may independently Oxygen (O) or sulfur (S).

The compound of formula (I) may be a nucleoside, a nucleotide (including a monophosphate, a diphosphate, a triphosphate, a thiomonophosphate, an alpha thiodiphosphate, and/or an alpha thiotriphosphate) ) or a nucleotide prodrug. In some embodiments, --- may be absent, Z ¹ may be absent, O ¹ may be OR ^1A , and R ^3A may be selected from H, halo, OH, -OC(=O)R " ^A and optionally substituted O-linked amino acids, R ^4A may be selected from OH, halo, -OC(=O)R" ^B and optionally substituted O-linked amino acids, or R ^3A And R ^4A may be an oxygen atom which forms a 5-membered ring via a carbonyl group.

When both are present, multiple substituents can be attached to the 5' position of formula (I). In some embodiments, R ^1A can be hydrogen. In some embodiments, R ^1A can be an optionally substituted thiol group. For example, R ^1A can be -C(=O)R ^39A , wherein R ^{39A can be} selected from optionally substituted C _1-12 alkyl, optionally substituted C _2-12 alkenyl, as appropriate Substituted C _2-12 alkynyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _5-8 cycloalkenyl, optionally substituted C _6-10 aryl, optionally Substituted heteroaryl, optionally substituted heterocyclic, optionally substituted aryl (C _1-6 alkyl), optionally substituted heteroaryl (C _1-6 alkyl) and optionally Substituted heterocyclic group (C _1-6 alkyl). In some embodiments, R ^39A can be a substituted C _1-12 alkyl group. In other embodiments, R ^39A can be an unsubstituted C _1-12 alkyl group. In some embodiments, R ^1A can be -C(=O)-unsubstituted C _1-4 alkyl. In some embodiments, both R ^a1 and R ^a2 can be hydrogen. In other embodiments, R ^a1 can be hydrogen and R ^a2 can be deuterium. In other embodiments, both R ^a1 and R ^{a2 may} be deuterium.

In other embodiments, R ^1A can be an optionally substituted O-linked amino acid. Examples of suitable O-linked amino acids include alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, serine, and cheese. Amine acid, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hydroxyresinamine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta- Alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine. In some embodiments, the O-linked amino acid can have a structure Wherein R ^40A may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C ₆ aryl, optionally substituted C ₁₀ aryl and optionally substituted aryl (C _1-6 alkyl); and R ^41A can be hydrogen or optionally substituted C _1-4 alkane Or R ^40A and R ^41A may be combined to form an optionally substituted C _3-6 cycloalkyl group. It is understood by those skilled in the art that when R ^1A is an optionally substituted O-linked amino acid, the oxygen of R ^1A O- of formula (I) is a moiety of an optionally substituted O-linked amino acid. For example, when R ^1A is When the "*" indicates oxygen, it is the oxygen of R ^1A O- of the formula (I).

When R ^40A is substituted, R ^40A may be substituted with one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^40A can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^40A can be hydrogen. In other embodiments, R ^40A can be a methyl group. In some embodiments, R ^41A can be hydrogen. In other embodiments, R ^41A can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^41A can be methyl. Depending on the group selected for R ^40A and R ^41A , the carbon to which R ^40A and R ^{41A are} attached may be the palm center. In some embodiments, the carbon to which R ^40A and R ^{41A are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^40A and R ^{41A are} attached may be the (S)-pair palm center.

Suitable for Examples include the following: , ,

In some embodiments, R ^1A can be . In some embodiments, both R ^6A and R ^7A can be hydrogen. In other embodiments, neither R ^{6A nor} R ^7A may be present. In other embodiments, at least one of R ^6A and R ^7A may be absent. In other embodiments, at least one of R ^6A and R ^7A can be hydrogen. It is understood by those skilled in the art that when R ^6A and/or R ^{7A are} not present, the associated oxygen will have a negative charge. For example, when R ^6A is absent, the oxygen associated with R ^6A will have a negative charge. In some embodiments, Z ^1A can be O (oxygen). In other embodiments, Z ^1A can be S (sulfur). In some embodiments, R ^1A can be a monophosphate. In other embodiments, R ^1A can be a monothiophosphate.

In some embodiments, R ^1A can be ;R ^6A can be R ^7A may be absent or hydrogen; R ^12A and R ^13A may be independently absent or hydrogen; R ^14A may be O ^- , OH or methyl; and m may be 0 or 1. In some embodiments, m can be 0, and R ^7A , R ^{12A ,} and R ^13A can be independently absent or hydrogen. In other embodiments, m can be 1, and R ^7A , R ^{12A ,} and R ^13A can be independently absent or hydrogen; and R ^14A can be O ⁻ , OH, or methyl. In some embodiments, m can be 1, and R ^7A , R ^{12A ,} and R ^13A can be independently absent or hydrogen; and R ^14A can be O ⁻ or OH. In other embodiments, m can be 1, and R ^7A , R ^{12A ,} and R ^13A can be independently absent or hydrogen; and R ^14A can be methyl. It is understood by those skilled in the art that when m is 0, R ^6A can be a diphosphate (when Z ^1A is oxygen) or an alpha thiodiphosphate (when Z ^1A is sulfur). Similarly, those skilled in the art understand that when m is 1, R ^6A can be a triphosphate (when Z ^1A is oxygen) or an alpha thiotriphosphate (when Z ^1A is sulfur).

In some embodiments, when R ^1A is One of R ^6A and R ^7A may be hydrogen, and the other of R ^6A and R ^7A may be selected from optionally substituted C _1-24 alkyl, optionally substituted C _2-24 Alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, A substituted heteroaryl group and optionally an substituted aryl group (C _1-6 alkyl group). In some embodiments, one of R ^6A and R ^7A can be hydrogen, and the other of R ^6A and R ^7A can be an optionally substituted C _1-24 alkyl group. In other embodiments, R ^6A and R ^7A are each independently selected from optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 Alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted An aryl group (C _1-6 alkyl). In some embodiments, both R ^6A and R ^7A can be optionally substituted C _1-24 alkyl. In other embodiments, both R ^6A and R ^7A may be optionally substituted C _2-24 alkenyl. In some embodiments, R ^6A and R ^7A can independently be an optionally substituted group selected from the group consisting of: myristyl oil, myristyl, palm oil, palmitate, sapienyl , oil-based, elaidyl, vaccenyl, linoleyl, α-linolenyl, arachidonyl, Eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl, stearin, Eicosyl, behenyl, tetracosyl and hexadecyl groups.

In some embodiments, at least one of R ^6A and R ^7A can be *-(CR ^15A R ^16A ) _p -OC _1-24 alkyl. In other embodiments, both R ^6A and R ^7A may be *-(CR ^15A R ^16A ) _p -OC _1-24 alkyl. In some embodiments, each R ^15A and each R ^16A can be hydrogen. In other embodiments, at least one of R ^15A and R ^16A can be an optionally substituted C _1-24 alkyl group. In other embodiments, at least one of R ^15A and R ^16A can be an alkoxy group (eg, benzamidineoxy). In some embodiments, p can be one. In other embodiments, p can be 2. In other embodiments, p can be 3.

In some embodiments, at least one of R ^6A and R ^7A can be *-(CR ^17A R ^18A ) _q -OC _2-24 alkenyl. In other embodiments, both R ^6A and R ^7A may be *-(CR ^17A R ^18A ) _q -OC _2-24 alkenyl. In some embodiments, each of R ^17A and each of R ^18A can be hydrogen. In other embodiments, at least one of R ^17A and R ^18A can be an optionally substituted C _1-24 alkyl group. In some embodiments, q can be one. In other embodiments, q can be two. In other embodiments, q can be three. When at least one of R ^6A and R ^7A is *-(CR ^15A R ^16A ) _p -OC _1-24 alkyl or *-(CR ^17A R ^18A ) _q -OC _2-24 alkenyl, C _{1- The 24} alkyl group may be selected from the group consisting of octyl, decyl, lauryl, myristyl, palmityl, stearyl, eicosyl, behenyl, tetracosyl, and hexadecyl, and The C _2-24 alkenyl group may be selected from the group consisting of myristyl oil, palm oil based, raw alkenyl, oleyl, oleyl, octadecyl, linoleyl, alpha-sub linoleyl, Carbacenyl, eicosylpentenyl, behenyl, and docosahexaenyl.

In some embodiments, when R ^1A is At least one of R ^6A and R ^7A may be selected from , and And the other of R ^6A and R ^7A may be selected from the group consisting of non-existent, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl and A substituted aryl group (C _1-6 alkyl).

In some embodiments, at least one of R ^6A and R ^7A can be or . In some embodiments, both R ^6A and R ^7A can be . When one or both of R ^6A and R ^7A are When R ^19A and R ^20A are independently selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; and R ^21A may be selected from hydrogen, optionally substituted C _{1- 24} alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl, and optionally Substituted -O-monocyclic heterocyclic group. In some embodiments, R ^19A and R ^20A can be hydrogen. In other embodiments, at least one of R ^19A and R ^20A can be an optionally substituted C _1-24 alkyl group or an optionally substituted aryl group. In some embodiments, R ^21A can be an optionally substituted C _1-24 alkyl group. In some embodiments, R ^21A can be an unsubstituted C _1-4 alkyl group. In other embodiments, R ^21A can be an optionally substituted aryl group. In other embodiments, R ^21A can be optionally substituted as -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl or, as appropriate, substituted -O-monocyclic heterocyclic group. In some embodiments, R ^21A can be unsubstituted -OC _1-4 alkyl.

In some embodiments, both R ^6A and R ^7A can be . When one or both of R ^6A and R ^7A are When R ^22A and R ^23A are independently selected from hydrogen, optionally substituted C _1-24 alkyl, and optionally substituted aryl; R ^24A can be independently selected from hydrogen, optionally substituted C _{1 -24} alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl and The -O-monocyclic heterocyclic group may be substituted; s may be 0, 1, 2 or 3; and Z ^4A may independently be O (oxygen) or S (sulfur). In some embodiments, R ^22A and R ^23A can be hydrogen. In other embodiments, at least one of R ^22A and R ^23A can be an optionally substituted C _1-24 alkyl group or an optionally substituted aryl group. In some embodiments, R ^24A can be an optionally substituted C _1-24 alkyl group. In some embodiments, R ^24A can be an unsubstituted C _1-4 alkyl group. In other embodiments, R ^24A can be an optionally substituted aryl group. In other embodiments, R ^24A can be optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl or, as appropriate, substituted -O-monocyclic heterocyclic group. In other embodiments, R ^24A can be . In some embodiments, R ^24A can be unsubstituted -OC _1-4 alkyl. In some embodiments, Z ^4A can be O (oxygen). In other embodiments, Z ^4A may be S (sulfur). In some embodiments, s can be zero. In other embodiments, s can be one. In other embodiments, s can be two. In other embodiments, s can be three. In some embodiments, s can be 0 and R ^24A can be . In some embodiments, one or both of R ^6A and R ^7A can be isopropoxycarbonyloxymethyl (POC). In some embodiments, both R ^6A and R ^7A can be isopropoxycarbonyloxymethyl (POC) and form a bis(isopropoxycarbonyloxymethyl) (bis(POC)) prodrug. In other embodiments, one or both of R ^6A and R ^7A may be pentyl methoxymethyl (POM). In some embodiments, both R ^6A and R ^7A can be pentyl methoxymethyl (POM) and form a bis(polypentanyloxymethyl) (bis(POM)) prodrug.

In some embodiments, both R ^6A and R ^7A can be . When one or both of R ^6A and R ^7A are When R ^27A1 and R ^27A2 are independently ^{-C≡N or} optionally substituted by a C _2-8 organic carbonyl group, a C _2-8 alkoxycarbonyl group and a C _2-8 organic aminocarbonyl group R ^28A may be selected from hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkenyl; and t may be 1 or 2. In some embodiments, R ^27A1 can be ^-C≡N and R ^27A2 can be an optionally substituted C _2-8 alkoxycarbonyl group, such as —C(=O)OCH ₃ . In other embodiments, R ^27A1 can be ^-C≡N , and R ^27A2 can be an optionally substituted C _2-8 organoaminocarbonyl group, such as —C(=O)NHCH ₂ CH ₃ and —C ( =O) NHCH ₂ CH ₂ phenyl. In some embodiments, both R ^27A1 and R ^{27A2 may} be optionally substituted C _2-8 organocarbonyl, such as —C(=O)CH ₃ . In some embodiments, both R ^27A1 and R ^{27A2 may} be optionally substituted C _1-8 alkoxycarbonyl, such as —C(=O)OCH ₂ CH ₃ and —C(=O)OCH ₃ . In some embodiments, including those described in this paragraph, R ^28A can be an optionally substituted C _1-4 alkyl group. In some embodiments, R ^28A can be methyl or a third butyl group. In some embodiments, t can be one. In other embodiments, t can be 2.

In some embodiments, R ^6A and R ^7A can each be an optionally substituted aryl group. In some embodiments, at least one of R ^6A and R ^7A can be an optionally substituted aryl group. For example, both R ^6A and R ^{7A may} be optionally substituted phenyl or optionally substituted naphthyl. When substituted, the substituted aryl group may be substituted with 1, 2, 3 or more substituents. When two or more substituents are present, the substituents may be the same or different. In some embodiments, when at least one of R ^6A and R ^7A is a substituted phenyl group, the substituted phenyl group can be a p-, o- or m-substituted phenyl group.

In some embodiments, R ^6A and R ^7A can each be an optionally substituted aryl (C _1-6 alkyl). In some embodiments, at least one of R ^6A and R ^7A can be an optionally substituted aryl (C _1-6 alkyl). For example, both R ^6A and R ^{7A may} be optionally substituted benzyl. When substituted, the substituted benzyl group may be substituted with 1, 2, 3 or more substituents. When two or more substituents are present, the substituents may be the same or different. In some embodiments, the aryl group of the aryl (C _1-6 alkyl) group can be a p-, o- or m-substituted phenyl group.

In some embodiments, both R ^6A and R ^7A can be . In some embodiments, at least one of R ^6A and R ^7A can be . In some embodiments, R ^25A can be hydrogen. In other embodiments, R ^25A can be an optionally substituted C _1-24 alkyl group. In other embodiments, R ^25A can be an optionally substituted aryl (eg, optionally substituted phenyl). In some embodiments, R ^25A can be C _1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched chain) And straight chain) and hexyl (branched chain and straight chain). In some embodiments, w can be zero. In other embodiments, w can be one. In some embodiments, both R ^6A and R ^7A can be S-mercaptothioethyl (SATE) and form a SATE ester prodrug.

In some embodiments, both R ^6A and R ^7A can be . In some embodiments, at least one of R ^6A and R ^7A can be . In some embodiments, R ^26A can be hydrogen. In other embodiments, R ^26A can be an optionally substituted C _1-24 alkyl group. In other embodiments, R ^26A can be an optionally substituted aryl group, such as optionally substituted phenyl. In some embodiments, R ^26A can be an optionally substituted C _1-6 alkyl group. In some embodiments, R ^26A can be an unsubstituted C _1-6 alkyl group. In some embodiments, y can be three. In other embodiments, y can be four. In other embodiments, y can be five.

In some embodiments, both R ^6A and R ^7A can be . In some embodiments, at least one of R ^6A and R ^7A can be . In some embodiments, R ^29A can be hydrogen. In other embodiments, R ^29A can be an optionally substituted C _1-24 alkyl group. In some embodiments, R ^29A can be a C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In other embodiments, R ^29A can be an optionally substituted aryl group, such as optionally substituted phenyl or optionally substituted naphthyl. In some embodiments, both R ^6A and R ^7A can be a meta-dioxolone group and form a meta-dioxolone prodrug.

In some embodiments, R ^6A and R ^7A may be combined to form an optionally substituted . For example, R ^1A can be replaced as appropriate . When substituted, the ring may be substituted 1, 2, 3 or more times. When substituted with a plurality of substituents, the substituents may be the same or different. In some embodiments, when R ^1A is The ring may be substituted with an optionally substituted aryl group and/or optionally substituted heteroaryl group. An example of a suitable heteroaryl group is pyridyl. In some embodiments, R ^6A and R ^7A may be combined to form an optionally substituted , such as And wherein R ^32A may be an optionally substituted aryl group, optionally substituted heteroaryl group or optionally substituted heterocyclic group. In some embodiments, R ^6A and R ^7A can form a cyclic 1-aryl-1,3-propyl ester (HepDirect) prodrug moiety.

In some embodiments, R ^6A and R ^7A may be combined to form an optionally substituted Wherein the oxygen, phosphorus and the moiety attached to R ^6A and R ^7A form a six to ten member ring system. Replaced as appropriate Examples include , , and . In some embodiments, R ^6A and R ^7A can form a cycloSal prodrug.

In some embodiments, R ^6A and R ^7A can be the same. In some embodiments, R ^6A and R ^7A can be different.

In some embodiments, Z ^1A can be oxygen. In other embodiments, Z ^1A can be sulfur.

In some embodiments, R ^1A can be . In some embodiments, R ^{8A can be} selected from the group consisting of non-existent, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkyne a C _3-6 cycloalkyl group optionally substituted, and optionally a C _3-6 cycloalkenyl group; and R ^9A may be independently selected from optionally substituted C _1-24 alkyl groups, as appropriate Substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, and optionally substituted C _3-6 cycloalkenyl.

In some embodiments, R ^8A can be hydrogen, and R ^9A can be an optionally substituted C _1-6 alkyl. Examples of suitable C _1-6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and linear) and hexyl (branched) Chain and straight chain). In other embodiments, R ^8A can be hydrogen, and R ^9A can be NR ^30A R ^31A , wherein R ^30A and R ^31A can be independently selected from hydrogen, optionally substituted C _1-24 alkyl, optionally Substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, and optionally Substituted aryl (C _1-4 alkyl). In some embodiments, one of R ^30A and R ^31A can be hydrogen and the other of R ^30A and R ^31A can be optionally substituted C _1-6 alkyl, optionally substituted C _{2 -6} alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, and optionally substituted phenyl base.

In some embodiments, R ^8A may be absent or hydrogen; and R ^9A may be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In other embodiments, R ^8A can be an optionally substituted aryl; and R ^9A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In other embodiments, R ^8A can be an optionally substituted heteroaryl; and R ^9A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. . In some embodiments, R ^{9A can be} selected from the group consisting of alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, serine, Tyrosic acid, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and their ester derivatives. Examples of the optionally substituted N-bonded amino acid ester derivative include the following substituted forms: N-propyl allylate, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-proline isopropyl ester and N-leucine isopropyl ester. In some embodiments, R ^9A can have a structure And wherein R ^33A may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted aryl, optionally substituted aryl ( C _1-6 alkyl) and optionally substituted haloalkyl; R ^34A may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally a substituted C _3-6 cycloalkyl group, optionally substituted C ₆ aryl group, optionally substituted C ₁₀ aryl group, and optionally substituted aryl group (C _1-6 alkyl group); ^35A can be hydrogen or optionally substituted C _1-4 alkyl; or R ^34A and R ^35A can be joined together to form an optionally substituted C _3-6 cycloalkyl.

When R ^34A is substituted, R ^34A may be substituted with one or more substituents selected from the group consisting of N-decylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^34A can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^34A can be hydrogen. In other embodiments, R ^34A can be a methyl group. In some embodiments, R ^33A can be an optionally substituted C _1-6 alkyl group. Examples of optionally substituted C _1-6 alkyl groups include the following optionally substituted variants: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , pentyl (branched and linear) and hexyl (branched and linear). In some embodiments, R ^33A can be methyl or isopropyl. In some embodiments, R ^33A can be ethyl or neopentyl. In other embodiments, R ^33A can be an optionally substituted C _3-6 cycloalkyl. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R ^33A can be an optionally substituted cyclohexyl group. In other embodiments, R ^33A can be an optionally substituted aryl group (such as phenyl and naphthyl). In other embodiments, R ^33A can be an optionally substituted aryl (C _1-6 alkyl). In some embodiments, R ^33A can be an optionally substituted benzyl group. In some embodiments, R ^33A can be an optionally substituted C _1-6 haloalkyl group, such as CF ₃ . In some embodiments, R ^35A can be hydrogen. In other embodiments, R ^35A can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^35A can be methyl. In some embodiments, R ^34A and R ^35A can be joined together to form an optionally substituted C _3-6 cycloalkyl group. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the group selected for R ^34A and R ^35A , the carbon to which R ^34A and R ^{35A are} attached may be the center of the palm. In some embodiments, the carbon to which R ^34A and R ^{35A are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^34A and R ^{35A are} attached may be the (S)-pair palm center.

In some embodiments, when R ^1A is When Z ^2A can be O (oxygen). In other embodiments, when R ^1A is When Z ^2A can be S (sulfur). In some embodiments, when R ^1A is The compound of formula (I) may be an amino phosphate prodrug such as an amino aryl phosphate prodrug.

In some embodiments, R ^1A can be . In some embodiments, R ^10A and R ^11A can each be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In some embodiments, R ^10A and R ^11A are independently selected from the group consisting of alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, and lysine. , serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and Its ester derivative. In some embodiments, R ^10A and R ^11A may be substituted as follows: N-propyl propylamine, cyclohexyl N-alanine, neopentyl N-alanine, N-decylamine Isopropyl acrylate and N-leucine. In some embodiments, R ^10A and R ^11A may independently have a structure Wherein R ^36A may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted aryl, optionally substituted aryl ( C _1-6 alkyl) and optionally substituted haloalkyl; R ^37A may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally a substituted C _3-6 cycloalkyl group, optionally substituted C ₆ aryl group, optionally substituted C ₁₀ aryl group, and optionally substituted aryl group (C _1-6 alkyl group); ^38A can be hydrogen or optionally substituted C _1-4 alkyl; or R ^37A and R ^38A can be joined together to form an optionally substituted C _3-6 cycloalkyl.

When R ^37A is substituted, R ^37A may be substituted with one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^37A can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^37A can be hydrogen. In other embodiments, R ^37A can be a methyl group. In some embodiments, R ^36A can be an optionally substituted C _1-6 alkyl group. Examples of optionally substituted C _1-6 alkyl groups include the following optionally substituted variants: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , pentyl (branched and linear) and hexyl (branched and linear). In some embodiments, R ^36A can be methyl or isopropyl. In some embodiments, R ^36A can be ethyl or neopentyl. In other embodiments, R ^36A can be an optionally substituted C _3-6 cycloalkyl. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R ^36A can be an optionally substituted cyclohexyl group. In other embodiments, R ^36A can be an optionally substituted aryl group (such as phenyl and naphthyl). In other embodiments, R ^36A can be an optionally substituted aryl (C _1-6 alkyl). In some embodiments, R ^36A can be an optionally substituted benzyl group. In some embodiments, R ^36A can be optionally substituted C _1-6 haloalkyl, such as CF ₃ . In some embodiments, R ^38A can be hydrogen. In other embodiments, R ^38A can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^38A can be methyl. In some embodiments, R ^37A and R ^38A can be joined together to form an optionally substituted C _3-6 cycloalkyl group. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the group selected for R ^37A and R ^38A , the carbon to which R ^37A and R ^{38A are} attached may be the center of the palm. In some embodiments, the carbon to which R ^37A and R ^{38A are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^37A and R ^{38A are} attached may be the (S)-pair palm center.

Suitable for and Examples of groups include the following:

In some embodiments, R ^10A and R ^11A can be the same. In some embodiments, R ^10A and R ^11A can be different.

In some embodiments, Z ^3A can be O (oxygen). In other embodiments, Z ^3A can be S (sulfur). In some embodiments, when R ^1A is The compound of formula (I) may be a prodrug phosphate prodrug.

A plurality of substituents may be present at the 4' position of the pentose ring. In some embodiments, R ^2A can be an unsubstituted C _1-4 alkyl group. Unsubstituted C _1-4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In other embodiments, R ^2A can be an unsubstituted C _2-4 alkenyl group such as a vinyl group, a propenyl group, and a butenyl group. In other embodiments, R ^2A can be an unsubstituted C _2-4 alkynyl group, such as ethynyl, propynyl, and butynyl. In other embodiments, R ^2A can be a haloalkyl group. Examples of haloalkyl groups are -(CH ₂ ) _1-6 halogen and -CHF ₂ . In some embodiments, the haloalkyl group can be -(CH ₂ ) _1-6 F or -(CH ₂ ) _1-6 Cl. In some embodiments, the haloalkyl group can be a fluoromethyl group. In other embodiments, R ^2A can be -CHF ₂ . In other embodiments, R ^2A can be a C _1-6 azidoalkyl group. For example, R ^2A can be an azidomethyl group, an azidoethyl group, an azidopropyl group, an azidobutyl group, an azidopentyl group or an azidohexyl group. In some embodiments, R ^2A can be a C _1-6 aminoalkyl group. For example, R ^2A can be aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl or aminohexyl. In other embodiments, R ^2A can be a halo group. For example, R ^2A can be fluorine (F) or chlorine (Cl). In other embodiments, R ^2A can be hydrogen. In other embodiments, R ^2A can be -CN. In some embodiments, R ^{2A can be} selected from halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, Substituted C _3-6 cycloalkyl, optionally substituted -OC _1-6 alkyl, optionally substituted -OC _3-6 alkenyl, optionally substituted -OC _3-6 alkynyl And cyano group.

A plurality of substituents may also be present at the 2' position of the pentose ring. In some embodiments, R ^4A can be OH. In other embodiments, R ^4A can be -OC(=O)R" ^B , wherein R" ^B can be an optionally substituted C _1-24 alkyl group. In some embodiments, R ^4A can be -OC(=O)R" ^B , wherein R" ^B can be an unsubstituted C _1-4 alkyl group. In other embodiments, R ^4A can be a halo group. In some embodiments, R ^4A can be F. In other embodiments, R ^4A can be Cl. In some embodiments, R ^4A can be N ₃ . In some embodiments, R ^4A can be NR" ^B1 R" ^B2 . For example, R ^4A can be NH ₂ . Other examples may be monosubstituted C _1-6 alkyl-amines or disubstituted C _1-6 alkyl-amines. In other embodiments, R ^4A can be hydrogen (H).

In other embodiments, R ^4A can be an optionally substituted O-linked amino acid, such as an O-linked alpha-amino acid. In some embodiments, the O-linked amino acid can have a structure Wherein R ^42A may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C ₆ aryl, optionally substituted C ₁₀ aryl and optionally substituted aryl (C _1-6 alkyl); and R ^43A can be hydrogen or optionally substituted C _1-4 alkane Or R ^42A and R ^43A may be joined together to form an optionally substituted C _3-6 cycloalkyl group.

When R ^42A is substituted, R ^42A may be substituted with one or more substituents selected from the group consisting of N-decylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^42A can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^42A can be hydrogen. In other embodiments, R ^42A can be a methyl group. In some embodiments, R ^43A can be hydrogen. In other embodiments, R ^43A can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^43A can be methyl. Depending on the group selected for R ^42A and R ^43A , the carbon to which R ^42A and R ^{43A are} attached may be the center of the palm. In some embodiments, the carbon to which R ^42A and R ^{43A are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^42A and R ^{43A are} attached may be the (S)-pair palm center.

Suitable for Examples include the following: , ,

In some embodiments, R ^5A can be H. In other embodiments, R ^5A can be a halo group, including F and Cl. In other embodiments, R ^5A can be an optionally substituted C _1-6 alkyl group. For example, R ^5A can be in the following substituted or unsubstituted form: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branches) Chain or linear) and hexyl (branched or linear). In some embodiments, R ^5A can be a halo substituted C _1-6 alkyl group, such as —CH ₂ F. In other embodiments, R ^5A can be an optionally substituted C _2-6 alkenyl group. In some embodiments, R ^5A can be an optionally substituted C _2-6 alkynyl group. For example, R ^5A can be an ethynyl group. In some embodiments, R ^5A can be a hydroxyl group (OH).

A plurality of substituents may also be present at the 1' position of the pentose ring. In some embodiments, R ^A can be hydrogen. In some embodiments, R ^A can be deuterium. In other embodiments, R ^A can be an unsubstituted C _1-3 alkyl group (such as methyl, ethyl, n-propyl, and isopropyl). In other embodiments, R ^A can be an unsubstituted C _2-4 alkenyl group (eg, vinyl, propenyl (branched or linear) and butenyl (branched or linear)). In some embodiments, R ^A can be an unsubstituted C _2-3 alkynyl group (such as ethynyl and propynyl (branched or linear)). In other embodiments, R ^A can be an unsubstituted cyano group.

In some embodiments, --- may not be present such that the compound of formula (I) has the structure: . When neither -------- is present, there may be multiple groups at the 3' position. In some embodiments, R ^3A can be H. In other embodiments, R ^3A can be a halo group. For example, R ^3A can be fluorine (F) or chlorine (Cl). In other embodiments, R ^3A can be OH. In some embodiments, R ^3A can be -OC(=O)R" ^A , wherein R" ^A can be an optionally substituted C _1-24 alkyl. In some embodiments, R ^3A can be -OC(=O)R" ^A , wherein R" ^A can be an unsubstituted C _1-4 alkyl group. In other embodiments, R ^3A can be an optionally substituted O-linked amino acid, such as an optionally substituted O-linked alpha-amino acid. The optionally substituted O-linked amino acid may have a structure Wherein R ^44A may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C ₆ aryl, optionally substituted C ₁₀ aryl and optionally substituted aryl (C _1-6 alkyl); and R ^45A can be hydrogen or optionally substituted C _1-4 alkane Or R ^44A and R ^45A may be joined together to form an optionally substituted C _3-6 cycloalkyl group.

When R ^44A is substituted, R ^44A may be substituted with one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^44A can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^44A can be hydrogen. In other embodiments, R ^44A can be a methyl group. In some embodiments, R ^45A can be hydrogen. In other embodiments, R ^45A can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^45A can be methyl. Depending on the group selected for R ^44A and R ^45A , the carbon to which R ^44A and R ^{45A are} attached may be the center of the palm. In some embodiments, the carbon to which R ^44A and R ^{45A are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^44A and R ^{45A are} attached may be the (S)-pair palm center.

Suitable for Examples include the following: , ,

In some embodiments, R ^3A and R ^4A can each be an oxygen atom that forms a 5-membered ring via a carbonyl linkage.

In some embodiments, R ^2A can be fluorine and R ^3A can be fluorine. In some embodiments, R ^2A can be fluorine and R ^4A can be fluorine. In some embodiments, R ^2A can be fluoro, R ^3A can be fluoro, and R ^5A can be optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl. In some embodiments, R ^2A can be fluoro, R ^4A can be fluoro, and R ^5A can be optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl. In some embodiments, R ^2A can be fluorine, R ^3A can be fluorine, and R ^4A can be OH or -OC(=O)R" ^B. In some embodiments, R ^2A can be fluorine and R ^3A can be OH or -OC(=O)R" ^A and R ^4A may be fluorine. In some embodiments, R ^4A and R ^5A can each be F. In some embodiments, R ^2A can be *-(CH ₂ ) _1-6 halogen (eg, -CH ₂ F), and R ^3A can be OH, -OC(=O)R" ^A, or optionally substituted The linked amino acid and R ^4A can be OH. In some embodiments, R ^2A can be -(CH ₂ ) _1-6 halogen (eg, -CH ₂ F), and R ^3A can be OH, -OC (=O) R" ^A or optionally substituted O-linked amino acid, R ^4A may be OH and R ^5A may be unsubstituted C _1-6 alkyl. In some embodiments, R ^2A can be -(CH ₂ ) _1-6 N ₃ (such as -CH ₂ N ₃ ), R ^3A can be OH, and R ^4A can be fluoro.

In some embodiments, --- may each be a single bond such that the compound of formula (I) has the structure: . When -------- is each a single bond, R ^3A may be oxygen (O). In some embodiments, when --- each is a single bond, R ^1B can be O ^- or OH. In other embodiments, when --- each is a single bond, R ^1B can be -O- optionally substituted C _1-6 alkyl. For example, R ^1B can be -O-unsubstituted C _1-6 alkyl.

In some embodiments, when -------- are each a single bond, R ^1B can be . In other embodiments, R ^1B can be . For example, R ^1B can be isopropoxycarbonyloxymethoxy or pentyleneoxymethoxy. In other embodiments, R ^1B can be . S-mercaptothioethyl (SATE) is An example of a base. In other embodiments, R ^1B can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, such as an optionally substituted N-linked alpha-amino group. An acid or an optionally substituted N-linked alpha-amino acid ester derivative.

Examples of optionally substituted N-linked amino acids and optionally substituted N-linked amino acid ester derivatives are described herein. In some embodiments, R ^{1B can be} selected from the group consisting of alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, serine, Tyrosic acid, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and their ester derivatives. In some embodiments, R ^1B may be substituted as follows: N-propyl propylamine, cyclohexyl N-alanine, neopentyl N-alanine, isopropyl N-proline Ester and isopropyl N- lysinate. In some embodiments, R ^1B can have a structure Wherein R ^10B may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted aryl, optionally substituted aryl ( C _1-6 alkyl) and optionally substituted haloalkyl; R ^11B may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally a substituted C _3-6 cycloalkyl group, optionally substituted C ₆ aryl group, optionally substituted C ₁₀ aryl group, and optionally substituted aryl group (C _1-6 alkyl group); ^12B may be hydrogen or optionally substituted C _1-4 alkyl; or R ^11B and R ^12B may be joined together to form an optionally substituted C _3-6 cycloalkyl.

As described herein, R ^11B can be substituted. Examples of the substituent include one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted heteroaryl, O-carboxyl And an amine group. In some embodiments, R ^11B can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^11B can be hydrogen. In other embodiments, R ^11B can be methyl. In some embodiments, R ^10B can be an optionally substituted C _1-6 alkyl group. In some embodiments, R ^10B can be methyl, ethyl, isopropyl or neopentyl. In other embodiments, R ^10B can be an optionally substituted C _3-6 cycloalkyl. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R ^10B can be an optionally substituted cyclohexyl group. In other embodiments, R ^10B can be an optionally substituted aryl group (such as phenyl and naphthyl). In other embodiments, R ^10B can be an optionally substituted aryl (C _1-6 alkyl) group, such as optionally substituted benzyl. In some embodiments, R ^10B can be optionally substituted C _1-6 haloalkyl, such as CF ₃ . In some embodiments, R ^12B can be hydrogen. In other embodiments, R ^12B can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^12B can be methyl. In some embodiments, R ^11B and R ^12B can be joined together to form an optionally substituted C _3-6 cycloalkyl group. Depending on the group selected for R ^11B and R ^12B , the carbon to which R ^11B and R ^{12B are} attached may be the center of the palm. In some embodiments, the carbon to which R ^11B and R ^{12B are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^11B and R ^{12B are} attached may be the (S)-pair palm center.

Suitable for Examples of groups include the following: ,

In some embodiments, R ^1B can be . In some embodiments, R ^9B can be hydrogen. In other embodiments, R ^9B can be an optionally substituted C _1-24 alkyl group. In other embodiments, R ^9B can be an optionally substituted aryl group, such as optionally substituted phenyl. In some embodiments, R ^9B can be an optionally substituted C _1-6 alkyl group. In some embodiments, R ^9B can be an unsubstituted C _1-6 alkyl group. In some embodiments, u can be 3. In other embodiments, u can be four. In other embodiments, u can be 5.

In some embodiments, Z ^1B can be oxygen (O). In other embodiments, Z ^1B can be S (sulfur).

A plurality of optionally substituted heterocyclic bases can be attached to the pentose ring. In some embodiments, one or more amine and/or amine groups of optionally substituted heterocyclic bases may be protected by a protecting group. For example, an amine group can be protected by converting an amine and/or an amine group to a guanamine or a urethane. In some embodiments, optionally substituted heterocyclic bases or optionally substituted heterocyclic bases can include increasing the solubility of the compound (eg, -(CH ₂ ) _1-2 -OP(=O)(OW ^1A) ) ₂ ). In some embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having one or more protected amine groups can have one of the following structures: Wherein: R ^A2 may be selected from the group consisting of hydrogen, halogen and NHR ^J2 , wherein R ^J2 may be selected from hydrogen, -C(=O)R ^K2 and -C(=O)OR ^L2 ; R ^B2 may be halogen or NHR ^W2 , wherein R ^W2 may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _3-8 cycloalkyl, -C(=O) R ^M2 and -C(=O)OR ^N2 ; R ^C2 may be hydrogen or NHR ^O2 , wherein R ^O2 may be selected from hydrogen, -C(=O)R ^P2 and -C(=O)OR ^Q2 ; R ^D2 may Selected from hydrogen, deuterium, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; R ^E2 may be selected from hydrogen , hydroxy, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, -C(=O)R ^R2 and -C(=O)OR ^S2 ; R ^F2 optional From hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; Y ² and Y ³ may independently N (nitrogen) or CR ^I2 , wherein R ^I2 may be selected from hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _{2 - 6} alkynyl; W ¹ may be NH, -NCH ₂ -OC(=O)CH(NH ₂ )-CH(CH ₃ ) ₂ Or -(CH ₂ ) _1-2 -OP(=O)(OW ^1A ) ₂ , wherein W ^1A may be selected from the absence of hydrogen and optionally substituted C _1-6 alkyl; R ^G2 may be optionally Substituted C _1-6 alkyl; R ^H2 may be hydrogen or NHR ^T2 , wherein R ^T2 may be independently selected from the group consisting of hydrogen, -C(=O)R ^U2 and -C(=O)OR ^V2 ; and R ^K2 And R ^L2 , R ^M2 , R ^N2 , R ^P2 , R ^Q2 , R ^R2 , R ^S2 , R ^U2 and R ^V2 may be independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, heteroaryl, heterocyclic, aryl (C _1-6 alkyl), heteroaryl (C _1-6 alkyl) and heterocyclic (C _1-6 alkyl). In some embodiments, the structures shown above can be modified by replacing one or more hydrogens with a substituent selected from the list of substituents provided in the definition of "substituted". Those skilled in the art understand that when W ^1A is absent, the oxygen atoms will have a negative charge associated with them. In some embodiments, a substituent on a base can result in the formation of a salt of a compound of formula (I).

In some embodiments, B ^1A can be an optionally substituted purine base. In other embodiments, B ^1A can be an optionally substituted pyrimidine base. In some embodiments, B ^1A can be . In other embodiments, B ^1A can be . In other embodiments, B ^1A can be , such as . In other embodiments, B ^1A can be Wherein W ¹ may be -NCH ₂ -OC(=O)CH(NH ₂ )-CH(CH ₃ ) ₂ or -(CH ₂ ) _1-2 -OP(=O)(OW ^1A ) ₂ . In some embodiments, B ^1A can be ,E.g or . In other embodiments, R ^D2 can be hydrogen. In other embodiments, B ^1A can be . In some embodiments, R ^B2 can be NH ₂ . In other embodiments, R ^B2 can be NHR ^W2 , where R ^W2 can be -C(=O)R ^M2 or -C(=O)OR ^N2 . In other embodiments, B ^1A can be . In some embodiments, B ^1A can be .

In some embodiments, a viral infection can be ameliorated or treated using a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: B ^1A can be an optionally substituted heterocyclic base or have a protected amine group. a heterocyclic base which is optionally substituted; --- may be absent or a single bond, and the restriction is two --- none or two --- --- are all single bonds; when -------- are not present, then Z ¹ may be absent, O ¹ may be OR ^1A , and R ^3A may be selected from H, halo, OH, -OC ( =O) R" ^A and optionally substituted O-linked amino acid, R ^4A may be selected from OH, halo, -OC(=O)R" ^B and optionally substituted O-linked amino acid , or R ^3A and R ^4A may each be an oxygen atom formed by a carbonyl linkage to form a 5-membered ring; when --- each is a single bond, then Z ¹ may be , O ¹ may be O, R ^3A may be O; R ^4A may be selected from OH, halo, -OC(=O)R" ^B, and optionally substituted O-linked amino acid; and R ^{1B is} optional a C _1-6 alkyl group which is optionally substituted from O ^- , OH, - O-, , , , And optionally substituted N-linked amino acid and optionally substituted N-bonded amino acid ester derivative; R ^1A may be selected from hydrogen, optionally substituted thiol, optionally substituted O bond Amino acid, , and ; R ^2A may be halo, unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, -(CH ₂ ) _1-6 halogen or -(CH ₂ ) _1-6 N ₃ R ^5A may be selected from H, halo, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; R ^6A , R ^7A and R ^8A may be independently selected from the group consisting of non-existent, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl , optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C _1-6 alkyl), optionally substituted *-(CR ^15A R ^16A ) _p -OC _1-24 alkyl, optionally substituted *-(CR ^17A R ^18A ) _q -OC _{1- 24} alkenyl, , and ; or R ^6A can be And R ^7A may be absent or hydrogen; or R ^6A and R ^7A may be combined to form a moiety selected from the group consisting of: And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6A and R ^7A form a six to ten member ring system; R ^9A can be independently selected from optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, NR ^30A R ^31A , a substituted N-linked amino acid and optionally an N-bonded amino acid ester derivative; R ^10A and R ^11A may independently be an optionally substituted N-linked amino acid and optionally a substituted N-linked amino acid ester derivative; R ^12A and R ^13A may be independently absent or hydrogen; R ^14A may be absent, hydrogen or methyl; each R ^15A , each R ^16A , each R ^17A and each R ^18A may independently be hydrogen, optionally substituted C _1-24 alkyl or alkoxy; R ^19A , R ^20A , R ^22A , R ^23A , R ^2B , R ^3B , R ^5B and R ^6B may independently An aryl group selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl, and optionally substituted; R ^21A and R ^4B are independently selected from hydrogen, optionally substituted C _1-24 alkyl, optionally. Substituted aryl, optionally substituted -OC _1-24 alkane And optionally substituted -O-aryl, optionally substituted -O-heteroaryl and optionally substituted -O-monocyclic heterocyclyl; R ^24A and R ^7B may be independently selected from hydrogen , optionally substituted C _1-24 alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl, optionally substituted -O-monocyclic heterocyclic group and ; R ^25A , R ^26A , R ^29A , R ^8B and R ^9B may be independently selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^27A1 and R ^27A2 may independently Selected as -C≡N, optionally substituted C _2-8 organic carbonyl, optionally substituted C _2-8 alkoxycarbonyl, and optionally substituted C _{2-8organidoaminocarbonyl} ; R ^28A Is selected from hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 a cycloalkyl group and optionally a substituted C _3-6 cycloalkenyl group; R ^30A and R ^31A may be independently selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, and optionally substituted C _3-6 cycloalkenyl; R" ^A and R" ^B may independently be optionally substituted C _1-24 alkyl; m, v and w may be 0 or 1; p and q may independently be 1, 2 or 3; r and s may independently 0, 1, 2 or 3; t is 1 or 2; u and y can independently be 3, 4 or 5; and Z ^1A , Z ^2A , Z ^3A , Z ^4A , Z ^1B and Z ^2B It may independently be O or S; wherein the viral infection may be caused by a virus selected from the group consisting of a picornavirus and a Flaviviridae virus; and the restriction condition is that when the Flaviviridae virus is a hepatitis C virus, the formula (I) The compound or a pharmaceutically acceptable salt thereof cannot be selected from the compounds of paragraphs C and F or a pharmaceutically acceptable salt thereof.

In some embodiments, a viral infection can be ameliorated or treated using a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: B ^1A can be an optionally substituted heterocyclic base or have a protected amine group. a heterocyclic base which is optionally substituted; --- may be absent or a single bond, and the restriction is two --- none or two --- --- are all single bonds; when -------- are not present, then Z ¹ may be absent, O ¹ may be OR ^1A , and R ^3A may be selected from H, halo, OH, -OC ( =O) R" ^A and optionally substituted O-linked amino acids, R ^4A may be selected from OH, halo, N ₃ , -OC(=O)R" ^B , optionally substituted O-bonds The amino acid and NR" ^B1 R" ^B2 , or R ^3A and R ^4A may be an oxygen atom formed by a carbonyl linkage to form a 5-membered ring; when --- each is a single bond, then Z ¹ may be O ¹ may be O, R ^3A may be O; R ^4A may be selected from OH, halo, N ₃ , -OC(=O)R" ^B , optionally substituted O-linked amino acid and NR" ^B1 R"^B2; and R ^1B may be selected from O ^- , OH, -O-, optionally substituted as C _1-6 alkyl, And optionally substituted N-linked amino acids and optionally substituted N-linked amino acid ester derivatives; R ^a1 and R ^a2 may independently be hydrogen or deuterium; R ^A may be hydrogen, deuterium or not Substituted C _1-3 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-3 alkynyl or cyano; R ^1A may be selected from hydrogen, optionally substituted thiol, O-linked amino acid, as appropriate, , and ; R ^2A may be hydrogen, halo, unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, -(CH ₂ ) _1-6 halogen, -(CH ₂ ) _1-6 N ₃ or -(CH ₂ ) _1-6 NH ₂ ; R ^5A may be selected from the group consisting of H, halo, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 Alkenyl and optionally substituted C _2-6 alkynyl; R ^6A , R ^7A and R ^8A are independently selected from the group consisting of non-existent, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted Aryl, optionally substituted heteroaryl, optionally substituted aryl (C _1-6 alkyl), optionally substituted *-(CR ^15A R ^16A ) _p -OC _1-24 alkyl, *- (CR ^17A R ^18A ) _q -OC _1-24 alkenyl, as appropriate , , ; or R ^6A can be And R ^7A may be absent or hydrogen; or R ^6A and R ^7A may be combined to form a moiety selected from the group consisting of: And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6A and R ^7A form a six to ten member ring system; R ^9A can be independently selected from optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, NR ^30A R ^31A , a substituted N-linked amino acid and optionally an N-bonded amino acid ester derivative; R ^10A and R ^11A may independently be an optionally substituted N-linked amino acid and optionally Substituted N-bonded amino acid ester derivatives; R ^12A and R ^13A may be independently absent or hydrogen; R ^14A may be O ^- , OH or methyl; each R ^15A , each R ^16A , each R ^17A and Each R ^18A may independently be hydrogen, optionally substituted C _1-24 alkyl or alkoxy; R ^19A , R ^20A , R ^22A , R ^23A , R ^2B , R ^3B , R ^5B and R ^6B may be independently Is selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^21A and R ^4B may be independently selected from hydrogen, optionally substituted C _1-24 alkyl, optionally a substituted aryl group, optionally substituted -OC _1-24 alkyl, Optionally substituted -O-aryl, optionally substituted -O-heteroaryl and optionally substituted -O-monocyclic heterocyclyl; R ^24A and R ^7B may be independently selected from hydrogen, Substituted C _1-24 alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O a heteroaryl group, optionally substituted -O-monocyclic heterocyclic group and ; R ^25A , R ^26A , R ^29A , R ^8B and R ^9B may be independently selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^27A1 and R ^27A2 may independently Selected as -C≡N, optionally substituted C _2-8 organic carbonyl, optionally substituted C _2-8 alkoxycarbonyl, and optionally substituted C _{2-8organidoaminocarbonyl} ; R ^28A It may be selected from hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 a cycloalkyl group and optionally a substituted C _3-6 cycloalkenyl group; R ^30A and R ^31A may be independently selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, and optionally substituted C _3-6 cycloalkenyl; R" ^A and R" ^B may independently be a substituted C _1-24 alkyl group; R" ^B1 and R" ^B2 may independently be hydrogen and optionally substituted C _1-6 alkyl; m, v and w may be used. 0 or 1; p and q may independently be 1, 2 or 3; r and s may independently be 0, 1, 2 or 3; t may be 1 or 2; u and y Is independently 3, 4 or 5; and ^{Z 1A, Z 2A, Z 3A} , Z 4A, Z 1B and Z ^2B can be independently O or S; wherein the viral infection is selected from the Picornaviridae virus and a flavivirus a virus caused by a virus; and the restriction condition is that when the Flaviviridae virus is a hepatitis C virus, the compound of the formula (I) or a pharmaceutically acceptable salt thereof cannot be selected from the group C, the D segment, the first a compound of paragraph E and paragraph G or a pharmaceutically acceptable salt thereof.

In some embodiments, when R ^2A is halo (such as fluorine); --- is absent; Z ¹ is absent; O ¹ is OR ^1A ; B ^1A is selected from the group consisting of Replace it as appropriate Replace it as appropriate Replace it as appropriate Replace it as appropriate And replaced by circumstances Wherein R ^a2 is optionally substituted C _1-6 alkyl or optionally substituted C _3-6 cycloalkyl, and R ^a3 and R ^a4 are independently selected from hydrogen, unsubstituted C _1-6 An alkyl group, an unsubstituted C _3-6 alkenyl group, an unsubstituted C _3-6 alkynyl group, and an unsubstituted C _3-6 cycloalkyl group, R ^a5 is NHR ^a8 , and R ^a6 is hydrogen, halogen Or NHR ^a9 ; R ^a7 is NHR ^a10 ; R ^a8 is selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 alkenyl, optionally substituted C _3-6 Cycloalkyl, -C(=O)R ^a11 and -C(=O)OR ^a12 ; R ^a9 is selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 Alkenyl, optionally substituted C _3-6 cycloalkyl, -C(=O)R ^a13 and -C(=O)OR ^a14 ; R ^a10 is selected from hydrogen, optionally substituted C _1-6 Alkyl, optionally substituted C _3-6 alkenyl, optionally substituted C _3-6 cycloalkyl, -C(=O)R ^a15 and -C(=O)OR ^a16 ; X ^a1 is N Or -CR ^a17 ; R ^a17 is selected from the group consisting of hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; ^{R a11, R a12, R a13} , R a14, R a15 , and R ^a16 independently based Is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, heteroaryl, a heterocyclic group, an aryl group (C _1-6 alkyl group), a heteroaryl group (C _1-6 alkyl group), and a heterocyclic group (C _1-6 alkyl group); then R ^3A is selected from H, a halogen group And optionally substituted O-linked amino acid; and R ^4A is selected from the group consisting of OH, halo, -OC(=O)R" ^A, and optionally substituted O-linked amino acid; or R ^4A An optionally substituted O-linked amino acid; and R ^3A is selected from the group consisting of H, halo, OH, -OC(=O)R" ^A and, optionally, an O-linked amino acid; or R ^3A and R ^4A are each an oxygen atom formed by a carbonyl linkage to form a 5-membered ring; or R ^1A is Where R ^6A and R ^{7A are} independently Where s is 1, 2 or 3, or Or R ^1A is Wherein R ^6A and R ^7A are taken together to form a moiety selected from the group consisting of: And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6A and R ^7A form a six to ten member ring system. In some embodiments, when R ^2A is halo (such as fluorine); --- each is a single bond; then R ^4A is -OC(=O)R" ^B or optionally substituted O-bonded amino acid. In some embodiments, when R ^2A is unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, -(CH ₂ ) _1-6 halogen or -(CH ₂ ) _1-6 N ₃ ;-------- are absent; Z ¹ is absent; O ¹ is OR ^1A ; R ^3A is OH, - OC(=O)R" ^A or an optionally substituted O-linked amino acid; and R ^4A is a halogen group; then R ^5A is selected from the group consisting of C _1-6 alkane as the case may be substituted a C _2-6 alkenyl group optionally substituted, and optionally a C _2-6 alkynyl group. In some embodiments, when R ^2A is unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, —(CH ₂ ) _{1- 6} halogen, -(CH ₂ ) _1-6 N ₃ ;-------- are absent; Z ¹ is absent; O ¹ is OR ^1A ; R ^4A is a halogen group; and R ^5A is H or halogen Base time; then R ^3A is H or a halogen group. In some embodiments, when R ^2A is unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, —(CH ₂ ) _{1- 6} halogen or -(CH ₂ ) _1-6 N ₃ ;-------- are absent; Z ¹ is absent; O ¹ is OR ^1A ; R ^3A is OH, -OC(=O)R" ^A or an optionally substituted O-linked amino acid; R ^4A is a halogen group; R ^5A is H or a halogen group; and R ^1A is At least one of R ^6A and R ^7A is Wherein R ^21A independently selects an optionally substituted -O-heteroaryl group and optionally an -O-monocyclic heterocyclic group; or at least one of R ^6A and R ^7A is Where s is 1, 2 or 3; or at least one of R ^6A and R ^7A is Wherein s is 0 and R ^24A is optionally substituted -O-heteroaryl or optionally substituted -O-monocyclic heterocyclyl. In some embodiments, when R ^2A is unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, —(CH ₂ ) _{1- 6} halogen or -(CH ₂ ) _1-6 N ₃ ;-------- are absent; Z ¹ is absent; O ¹ is OR ^1A ; R ^3A is OH, -OC(=O)R" ^A or an optionally substituted O-linked amino acid; R ^4A is a halogen group; R ^5A is H or a halogen group; and R ^1A is Time; then R ^8A is Wherein R ^{21A is} independently selected from optionally substituted -O-heteroaryl and optionally substituted -O-monocyclic heterocyclyl; or R ^8A is Where s is 1, 2 or 3; or R ^8A is Wherein s is 0 and R ^24A is optionally substituted -O-heteroaryl, optionally substituted -O-monocyclic heterocyclyl or . In some embodiments, when -------- is absent; Z ¹ is absent; O ¹ is OH; R ^2A is methyl; R ^3A is OH; then R ^4A is halo, -OC (=O)R" ^B or optionally substituted O-linked amino acid. In some embodiments, when -------- is absent; Z ¹ is absent; O ¹ is OR ^1A R ^2A is a halo group (for example, F); R ^3A is OH or -OC(=O)R"^A; R ^4A is a halo group (for example, F); and R ^5A is a methyl group, an ethyl group or a vinyl group; Then R ^1A cannot be selected from H, and Wherein R ^8A is an unsubstituted aryl group; R ^9A is And Z ^2A is oxygen. In some embodiments, such as when R ^3A is halo (such as fluorine) and R ^4A is OH, R ^{1A is} not hydrogen (H). In some embodiments, such as when R ^4A is halo (such as fluorine) and R ^3A is OH, R ^{1A is} not Where Z ^1A is O and R ^6A is . In some embodiments, R ^{2A is} not hydrogen (H). In some embodiments, R ^{2A is} not halogen. In some embodiments, R ^{2A is} not fluorine (F). In some embodiments, R ^{2A is} not -CN. In some embodiments, R ^{2A is} not -CHF ₂ . In some embodiments, R ^{5A is} not hydrogen or halo. In some embodiments, R ^{5A is} not -OH. In some embodiments, R ^{4A is} not hydrogen (H). In some embodiments, R ^{4A is} not halo. In some embodiments, R ^{4A is} not fluorine (F). In some embodiments, R ^{4A is} not chlorine (Cl). In some embodiments, R ^{2A is} not an unsubstituted C _1-4 alkyl group. In some embodiments, R ^{2A is} not an unsubstituted C _2-4 alkenyl group. In some embodiments, R ^{2A is} not an unsubstituted C _2-4 alkynyl group. In some embodiments, R ^{2A is} not -(CH ₂ ) _1-6 halogen. In some embodiments, R ^{2A is} not -(CH ₂ ) _1-6 N ₃ . In some embodiments, when R ^5A is fluoro, R ^{4A is} not hydrogen. In some embodiments, R ^{6A is} not an optionally substituted aryl group. In some embodiments, R ^{6A is} not an unsubstituted aryl group. In some embodiments, R ^{9A is} not N-alanine isopropyl ester. In some embodiments, R ^{5A is} not optionally substituted C _1-6 alkyl. For example, R ^{5A is} not an unsubstituted C _1-6 alkyl group such as a methyl group. In some embodiments, B ^{1A is} not an optionally substituted uracil, such as a halo substituted uracil. In some embodiments, when R ^1A is hydrogen, optionally substituted thiol, , where R ^6A can be ,or Wherein R ^8A is unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl and R ^9A is optionally substituted N-linked amino acid or optionally substituted N-linked amino acid ester R ^2A is fluorine, R ^3A is OH or -C(=O)-unsubstituted or substituted phenyl; R ^4A is fluorine; and R ^5A is C _1-4 alkyl (such as methyl); B ^1A cannot be a pyrimidine base that is optionally substituted, such as or . In some embodiments, when R ^1A is ^Where R ^2A is H, R ^3A is OH and R ^4A is OH or halogen (such as F), then R ^{5A is} not optionally substituted C _1-6 alkyl, optionally substituted C _2-6 olefin A C _2-6 alkynyl group substituted or optionally substituted.

Some embodiments disclosed herein are for use with a compound of formula (II), or a pharmaceutically acceptable salt thereof, and a compound of formula (II) or a pharmaceutically acceptable salt thereof:

Wherein: B ^1C may be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having a protected amine group; --- may be absent or a single bond, the limitation thereof For both -------- not exist or both -------- are single keys; when -------- does not exist, then Z ² does not exist, O ² may be OR ^1C , and R ^3C may be selected from H, halo, OH, N ₃ , -OC(=O)R" ^C , optionally substituted O-linked amino acid, and NR" ^D1 R" ^D2 , R ^4C may be selected from H, OH, halo, -OC(=O)R" ^D , optionally substituted O-linked amino acid and NR" ^D1 R" ^D2 , or R ^3C and R ^4C Forming a 5-membered ring oxygen atom via a carbonyl linkage; when -------- is a single bond, then Z ² can be O ² may be O, R ^3C may be O; R ^4C may be selected from OH, halo, N ₃ , -OC(=O)R" ^D and optionally substituted O-linked amino acid; and R ^1D may be selected from O ^- , OH, -O-, optionally substituted by C _1-6 alkyl, , , , And optionally substituted N-linked amino acid and optionally substituted N-bonded amino acid ester derivative; R ^c1 and R ^c2 may independently be hydrogen or deuterium; R ^C may be hydrogen, deuterium or not Substituted C _1-3 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-3 alkynyl or cyano; R ^1C may be selected from hydrogen, optionally substituted thiol, O-linked amino acid, as appropriate, , and ; R ^2C may be halo, unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, -CHF ₂ , -(CH ₂ ) _1-6 halogen, -(CH ₂ ) _1-6 N ₃ , -(CH ₂ ) _1-6 NH ₂ or -CN; R ^5C may be selected from H, halo, OH, optionally substituted C _{1- a 6} alkyl group, optionally substituted C _2-6 alkenyl group, and optionally substituted C _2-6 alkynyl group; R ^6C , R ^7C and R ^8C may be independently selected from the absence, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl (C _1-6 alkyl), optionally substituted *-(CR ^15C R ^16C ) _f -OC _1-24 alkyl, optionally substituted *-(CR ^17C R ^18C ) _g -OC _1-24 alkenyl, , , ; or R ^6C can be And R ^7C may be absent or hydrogen; or R ^6C and R ^7C may be combined to form a moiety selected from the group consisting of: And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6C and R ^7C form a six to ten member ring system; R ^9C may be independently selected from optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, NR ^30C R ^31C , a substituted N-linked amino acid and optionally an N-bonded amino acid ester derivative; R ^10C and R ^11C may independently be optionally substituted N-linked amino acids and optionally a substituted N-linked amino acid ester derivative; R ^12C and R ^13C may be independently absent or hydrogen; R ^14C may be O ^- , OH or methyl; each R ^15C , each R ^16C , each R ^17C and Each R ^18C may independently be hydrogen, optionally substituted C _1-24 alkyl or alkoxy; R ^19C , R ^20C , R ^22C , R ^23C , R ^2D , R ^3D , R ^5D and R ^6D may be independently Is selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^21C and R ^4D may be independently selected from hydrogen, optionally substituted C _1-24 alkyl, optionally a substituted aryl group, optionally substituted -OC _1-24 alkyl, Optionally substituted -O-aryl, optionally substituted -O-heteroaryl and optionally substituted -O-monocyclic heterocyclyl; R ^24C and R ^7D may be independently selected from hydrogen, Substituted C _1-24 alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O a heteroaryl group, optionally substituted -O-monocyclic heterocyclic group and ; R ^25C , R ^26C , R ^29C , R ^8D and R ^9D may be independently selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^27C1 and R ^27C2 may independently An optionally substituted C _2-8 organocarbonyl group, optionally substituted C _2-8 alkoxycarbonyl, and optionally substituted C _2-8 organoaminocarbonyl; R ^28C It may be selected from hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 Cycloalkyl and optionally substituted C _3-6 cycloalkenyl; R ^30C and R ^31C may be independently selected from hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 Alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, and optionally substituted aryl (C _1-4 alkyl); R" ^C and each R" ^D may independently be optionally substituted C _1-24 alkyl; each R" ^D1 and each R" ^D2 may independently be hydrogen or optionally substituted the C _1-6 alkyl group; c, d and e can be independently 0 or 1; f and g are independently 1, 2 or 3; h and j independently 2 or 3; b may be 1 or 2; k and l are independently 3, 4 or 5; and ^{Z 1C, Z 2C, Z 3C} , Z 4C, Z 1D and Z ^2D may independently be Oxygen (O) or sulfur (S).

The compound of formula (II) may be a nucleoside, a nucleotide (including a monophosphate, a diphosphate, a triphosphate, a thiomonophosphate, an alpha-thiodiphosphate, and/or an alpha-thiotriphosphate) ) or a nucleotide prodrug. In some embodiments, --- may be absent, Z ² may be absent, O ² may be OR ^1C , and R ^3C may be selected from H, halo, OH, -OC(=O)R " ^C and optionally substituted O-linked amino acids, R ^4C may be selected from OH, halo, -OC(=O)R" ^D and optionally substituted O-linked amino acids, or R ^3C And R ^4C may be an oxygen atom which forms a 5-membered ring via a carbonyl group.

When neither is present, multiple substituents may be attached to the 5' position of formula (II). In some embodiments, R ^1C can be hydrogen. In some embodiments, R ^1C can be an optionally substituted thiol group. For example, R ^1C can be -C(=O)R ^39C , wherein R ^{39C can be} selected from optionally substituted C _1-12 alkyl, optionally substituted C _2-12 alkenyl, as appropriate Substituted C _2-12 alkynyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _5-8 cycloalkenyl, optionally substituted C _6-10 aryl, optionally Substituted heteroaryl, optionally substituted heterocyclic, optionally substituted aryl (C _1-6 alkyl), optionally substituted heteroaryl (C _1-6 alkyl) and optionally Substituted heterocyclic group (C _1-6 alkyl). In some embodiments, R ^39C can be a substituted C _1-12 alkyl group. In other embodiments, R ^39C can be an unsubstituted C _1-12 alkyl group. In some embodiments, R ^1C can be -C(=O)-unsubstituted C _1-4 alkyl. In some embodiments, both R ^c1 and R ^c2 can be hydrogen. In other embodiments, R ^c1 can be hydrogen and R ^c2 can be deuterium. In other embodiments, both R ^c1 and R ^{c2 may} be deuterium.

In other embodiments, R ^1C can be an optionally substituted O-linked amino acid. Examples of suitable O-linked amino acids include alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, serine, and cheese. Amine acid, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hydroxyresinamine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta- Alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine. In some embodiments, the O-linked amino acid can have a structure Wherein R ^40C may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C ₆ aryl, optionally substituted C ₁₀ aryl and optionally substituted aryl (C _1-6 alkyl); and R ^41C can be hydrogen or optionally substituted C _1-4 alkane Or R ^40C and R ^41C may be combined to form an optionally substituted C _3-6 cycloalkyl group. It is understood by those skilled in the art that when R ^1C is an optionally substituted O-linked amino acid, the oxygen of R ^1C O- of formula (II) is a part of the optionally substituted O-linked amino acid. . For example, when R ^1C is The oxygen indicated by "*" is the oxygen of R ^1C O- of the formula (I).

When R ^40C is substituted, R ^40C may be substituted with one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^40C can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^40C can be hydrogen. In other embodiments, R ^40C can be a methyl group. In some embodiments, R ^41C can be hydrogen. In other embodiments, R ^41C can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^41C can be methyl. Depending on the group selected for R ^40C and R ^41C , the carbon to which R ^40C and R ^{41C are} attached may be the center of the palm. In some embodiments, the carbon to which R ^40C and R ^{41C are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^40C and R ^{41C are} attached may be the (S)-pair palm center.

Suitable for Examples include the following: , ,

In some embodiments, R ^1C can be . In some embodiments, both R ^6C and R ^7C can be hydrogen. In other embodiments, neither R ^{6C nor} R ^7C may be present. In other embodiments, at least one of R ^6C and R ^7C may be absent. In other embodiments, at least one of R ^6C and R ^7C can be hydrogen. It is understood by those skilled in the art that when R ^6C and/or R ^{7C are} not present, the associated oxygen will have a negative charge. For example, when R ^6C is absent, the oxygen bound to R ^6C will have a negative charge. In some embodiments, Z ^1C can be O (oxygen). In other embodiments, Z ^1C can be S (sulfur). In some embodiments, R ^1C can be a monophosphate. In other embodiments, R ^1C can be a monothiophosphate.

In some embodiments, R ^1C can be ; R ^6C can be R ^7C may be absent or hydrogen; R ^12C and R ^13C may be independently absent or hydrogen; R ^14C may be O ^- , OH or methyl; and e may be 0 or 1. In some embodiments, e can be 0, and R ^7C , R ^{12C ,} and R ^13C can be independently absent or hydrogen. In other embodiments, e can be 1, and R ^7C , R ^{12C ,} and R ^13C can be independently absent or hydrogen; and R ^14C can be O ⁻ , OH, or methyl. In some embodiments, e can be 1, and R ^7C , R ^{12C ,} and R ^13C can be independently absent or hydrogen; and R ^14C can be O ⁻ or OH. In other embodiments, e can be 1, and R ^7C , R ^{12C ,} and R ^13C can be independently absent or hydrogen; and R ^14C can be methyl. It is understood by those skilled in the art that when e is 0, R ^6C can be a diphosphate (when Z ^1C is oxygen) or an alpha thiodiphosphate (when Z ^1C is sulfur). Similarly, those skilled in the art understand that when e is 1, R ^6C can be a triphosphate (when Z ^1C is oxygen) or an alpha thiotriphosphate (when Z ^1C is sulfur).

In some embodiments, when R ^1C is One of R ^6C and R ^7C may be hydrogen, and the other of R ^6C and R ^7C may be selected from optionally substituted C _1-24 alkyl, optionally substituted C _2-24 Alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, A substituted heteroaryl group and optionally an substituted aryl group (C _1-6 alkyl group). In some embodiments, one of R ^6C and R ^7C can be hydrogen, and the other of R ^6C and R ^7C can be an optionally substituted C _1-24 alkyl group. In other embodiments, R ^6C and R ^7C are each independently selected from optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 Alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted An aryl group (C _1-6 alkyl). In some embodiments, both R ^6C and R ^7C are optionally substituted C _1-24 alkyl. In other embodiments, both R ^6C and R ^7C may be optionally substituted C _2-24 alkenyl. In some embodiments, R ^6C and R ^7C may independently be an optionally substituted group selected from the group consisting of: myristyl oil, myristyl, palm oil, palmitate, raw alkenyl, oil based , antioleyl, octadecyl, linoleyl, alpha- linoletenyl, eicosyltetraalkenyl, eicosapentaenyl, docosacenyl, docosahexaene Base, octyl, decyl, lauryl, stearin, eicosyl, behenyl, tetracosyl and hexadecyl.

In some embodiments, at least one of R ^6C and R ^7C can be *-(CR ^15C R ^16C ) _f -OC _1-24 alkyl. In other embodiments, both R ^6C and R ^7C may be *-(CR ^15C R ^16C ) _f -OC _1-24 alkyl. In some embodiments, each R ^15C and each R ^16C can be hydrogen. In other embodiments, at least one of R ^15C and R ^16C can be an optionally substituted C _1-24 alkyl group. In other embodiments, at least one of R ^15C and R ^16C can be an alkoxy group (eg, benzamidineoxy). In some embodiments, f can be one. In other embodiments, f can be 2. In other embodiments, f can be three.

In some embodiments, at least one of R ^6C and R ^7C can be *-(CR ^17C R ^18C ) _g -OC _2-24 alkenyl. In other embodiments, both R ^6C and R ^7C may be *-(CR ^17C R ^18C ) _g -OC _2-24 alkenyl. In some embodiments, each R ^17C and each R ^18C can be hydrogen. In other embodiments, at least one of R ^17C and R ^18C can be an optionally substituted C _1-24 alkyl group. In some embodiments, g can be one. In other embodiments, g can be 2. In other embodiments, g can be 3. When at least one of R ^6C and R ^7C is *-(CR ^15C R ^16C ) _f -OC _1-24 alkyl or *-(CR ^17C R ^18C ) _g -OC _2-24 alkenyl, C _{1- The 24} alkyl group may be selected from the group consisting of octyl, decyl, lauryl, myristyl, palmityl, stearyl, eicosyl, behenyl, tetracosyl, and hexadecyl, and The C _2-24 alkenyl group may be selected from the group consisting of myristyl oil, palm oil based, raw alkenyl, oleyl, oleyl, octadecyl, linoleyl, alpha-sub linoleyl, Carbacenyl, eicosylpentenyl, behenyl, and docosahexaenyl.

In some embodiments, when R ^1C is At least one of R ^6C and R ^7C may be selected from , and And the other of R ^6C and R ^7C may be selected from the group consisting of non-existent, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl and A substituted aryl group (C _1-6 alkyl).

In some embodiments, at least one of R ^6C and R ^7C can be or . In some embodiments, both R ^6C and R ^7C can be . When one or both of R ^6C and R ^7C are When R ^19C and R ^20C are independently selected from hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; and R ^21C may be selected from hydrogen, optionally substituted C _{1 - 24} alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl, and optionally Substituted -O-monocyclic heterocyclic group. In some embodiments, R ^19C and R ^20C can be hydrogen. In other embodiments, at least one of R ^19C and R ^20C can be an optionally substituted C _1-24 alkyl group or an optionally substituted aryl group. In some embodiments, R ^21C can be an optionally substituted C _1-24 alkyl group. In some embodiments, R ^21C can be an unsubstituted C _1-4 alkyl group. In other embodiments, R ^21C can be an optionally substituted aryl group. In other embodiments, R ^21C can be optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl or, as appropriate, substituted -O-monocyclic heterocyclic group. In some embodiments, R ^21C can be unsubstituted -OC _1-4 alkyl.

In some embodiments, both R ^6C and R ^7C can be . When one or both of R ^6C and R ^7C are When R ^22C and R ^23C are independently selected from hydrogen, optionally substituted C _1-24 alkyl, and optionally substituted aryl; R ^24C may be independently selected from hydrogen, optionally substituted C _{1 -24} alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl and The -O-monocyclic heterocyclic group may be substituted; h may be 0, 1, 2 or 3; and Z ^4C may independently be O (oxygen) or S (sulfur). In some embodiments, R ^22C and R ^23C can be hydrogen. In other embodiments, at least one of R ^22C and R ^23C can be an optionally substituted C _1-24 alkyl group or an optionally substituted aryl group. In some embodiments, R ^24C can be optionally substituted C _1-24 alkyl. In some embodiments, R ^24C can be an unsubstituted C _1-4 alkyl group. In other embodiments, R ^24C can be an optionally substituted aryl group. In other embodiments, R ^24C can be optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl or, as appropriate, substituted -O-monocyclic heterocyclic group. In other embodiments, R ^24C can be . In some embodiments, R ^24C can be unsubstituted -OC _1-4 alkyl. In some embodiments, Z ^4C can be O (oxygen). In other embodiments, Z ^4C may be S (sulfur). In some embodiments, h can be zero. In other embodiments, h can be one. In other embodiments, h can be 2. In other embodiments, h can be three. In some embodiments, h can be 0 and R ^24C can be . In some embodiments, one or both of R ^6C and R ^7C can be isopropoxycarbonyloxymethyl (POC). In some embodiments, both R ^6C and R ^7C can be isopropoxycarbonyloxymethyl (POC) and form bis(isopropoxycarbonyloxymethyl) (bis(POC)). In other embodiments, one or both of R ^6C and R ^7C may be pentyl methoxymethyl (POM). In some embodiments, both R ^6C and R ^7C may be pentyl methoxymethyl (POM) and form a bis(polypentanyloxymethyl) (bis(POM)) prodrug.

In some embodiments, both R ^6C and R ^7C can be . When one or both of R ^6C and R ^7C are ^Wherein , R ^27C1 and R ^27C2 may independently be ^{substituted by -C≡N or} optionally substituted with a C _2-8 organic carbonyl group, a C _2-8 alkoxycarbonyl group and a C _2-8 organic aminocarbonyl group. R ^28C may be selected from hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkenyl; and b may be 1 or 2. In some embodiments, R ^27C1 can be ^-C≡N , and R ^27C2 can be an optionally substituted C _2-8 alkoxycarbonyl group, such as —C(=O)OCH ₃ . In other embodiments, R ^27C1 can be ^-C≡N , and R ^27C2 can be an optionally substituted C _2-8 organoaminocarbonyl group, such as —C(=O)NHCH ₂ CH ₃ and —C ( =O) NHCH ₂ CH ₂ phenyl. In some embodiments, both R ^27C1 and R ^{27C2 may} be optionally substituted C _2-8 organocarbonyl, such as —C(=O)CH ₃ . In some embodiments, both R ^27C1 and R ^{27C2 may} be optionally substituted C _1-8 alkoxycarbonyl, such as —C(=O)OCH ₂ CH ₃ and —C(=O)OCH ₃ . In some embodiments, including the examples described in this paragraph, R ^28C can be an optionally substituted C _1-4 alkyl group. In some embodiments, R ^28C can be methyl or a third butyl group. In some embodiments, b can be one. In other embodiments, b can be 2.

In some embodiments, R ^6C and R ^7C can each be an optionally substituted aryl group. In some embodiments, at least one of R ^6C and R ^7C can be an optionally substituted aryl group. For example, both R ^6C and R ^7C may be optionally substituted phenyl or optionally substituted naphthyl. When substituted, the substituted aryl group may be substituted with 1, 2, 3 or more substituents. When two or more substituents are present, the substituents may be the same or different. In some embodiments, when at least one of R ^6C and R ^7C is a substituted phenyl group, the substituted phenyl group can be a p-, o- or m-substituted phenyl group.

In some embodiments, both R ^6C and R ^7C may be optionally substituted aryl (C _1-6 alkyl). In some embodiments, at least one of R ^6C and R ^7C can be an optionally substituted aryl (C _1-6 alkyl). For example, both R ^6C and R ^{7C may} be optionally substituted benzyl. When substituted, the substituted benzyl group may be substituted with 1, 2, 3 or more substituents. When two or more substituents are present, the substituents may be the same or different. In some embodiments, the aryl group of the aryl (C _1-6 alkyl) group can be a p-, o- or m-substituted phenyl group.

In some embodiments, both R ^6C and R ^7C can be . In some embodiments, at least one of R ^6C and R ^7C can be . In some embodiments, R ^25C can be hydrogen. In other embodiments, R ^25C can be an optionally substituted C _1-24 alkyl group. In other embodiments, R ^25C can be an optionally substituted aryl (eg, optionally substituted phenyl). In some embodiments, R ^25C can be C _1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched chain) And straight chain) and hexyl (branched chain and straight chain). In some embodiments, d can be zero. In other embodiments, d can be one. In some embodiments, both R ^6C and R ^7C can be S-mercaptothioethyl (SATE) and form a SATE ester prodrug.

In some embodiments, both R ^6C and R ^7C can be . In some embodiments, at least one of R ^6C and R ^7C can be . In some embodiments, R ^26C can be hydrogen. In other embodiments, R ^26C can be an optionally substituted C _1-24 alkyl group. In other embodiments, R ^26C can be an optionally substituted aryl group, such as optionally substituted phenyl. In some embodiments, R ^26C can be optionally substituted C _1-6 alkyl. In some embodiments, R ^26C can be an unsubstituted C _1-6 alkyl group. In some embodiments, l can be three. In other embodiments, l can be four. In other embodiments, l can be five.

In some embodiments, both R ^6C and R ^7C can be . In some embodiments, at least one of R ^6C and R ^7C can be . In some embodiments, R ^29C can be hydrogen. In other embodiments, R ^29C can be an optionally substituted C _1-24 alkyl group. In some embodiments, R ^29C can be a C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In other embodiments, R ^29C can be an optionally substituted aryl group, such as optionally substituted phenyl or optionally substituted naphthyl. In some embodiments, both R ^6C and R ^7C may be a meta-dioxolone group and form a meta-dioxolone prodrug.

In some embodiments, R ^6C and R ^7C may be combined to form an optionally substituted . For example, R ^1C can be replaced as appropriate . When substituted, the ring may be substituted 1, 2, 3 or more times. When substituted with a plurality of substituents, the substituents may be the same or different. In some embodiments, when R ^1C is The ring may be substituted with an optionally substituted aryl group and/or optionally substituted heteroaryl group. An example of a suitable heteroaryl group is pyridyl. In some embodiments, R ^6C and R ^7C may be combined to form an optionally substituted , such as And wherein R ^32C may be optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclic group. In some embodiments, R ^6C and R ^7C can form a cyclo 1-aryl-1,3-propyl ester (HepDirect) prodrug moiety.

In some embodiments, R ^6C and R ^7C may be combined to form an optionally substituted Wherein the oxygen, phosphorus and the moiety attached to R ^6C and R ^7C form a six to ten member ring system. Replaced as appropriate Examples include , , and . In some embodiments, R ^6C and R ^7C can form a cycloSal prodrug.

In some embodiments, R ^6C and R ^7C can be the same. In some embodiments, R ^6C and R ^7C can be different.

In some embodiments, Z ^1C can be oxygen. In other embodiments, Z ^1C can be sulfur.

In some embodiments, R ^1C can be . In some embodiments, R ^{8C can be} selected from the group consisting of non-existent, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkyne a C _3-6 cycloalkyl group optionally substituted, and optionally substituted C _3-6 cycloalkenyl; and R ^9C may be independently selected from optionally substituted C _1-24 alkyl, as appropriate Substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, and optionally substituted C _3-6 cycloalkenyl.

In some embodiments, R ^8C can be hydrogen, and R ^9C can be optionally substituted C _1-6 alkyl. Examples of suitable C _1-6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and linear) and hexyl (branched) Chain and straight chain). In other embodiments, R ^8C can be hydrogen, and R ^9C can be NR ^30C R ^31C , wherein R ^30C and R ^31C can be independently selected from hydrogen, optionally substituted C _1-24 alkyl, optionally Substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, and optionally Substituted aryl (C _1-4 alkyl). In some embodiments, R ^30C and R ^31C may one of hydrogen and the other of R ^30C and R ^31C may be in the optionally substituted alkyl group of C _1-6, optionally substituted C ₂ of _-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, and optionally substituted phenyl base.

In some embodiments, R ^8C may be absent or hydrogen; and R ^9C may be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In other embodiments, R ^8C can be an optionally substituted aryl; and R ^9C can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In other embodiments, R ^8C can be an optionally substituted heteroaryl; and R ^9C can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. . In some embodiments, R ^{9C can be} selected from the group consisting of alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, serine, Tyrosic acid, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and their ester derivatives. Examples of the optionally substituted N-bonded amino acid ester derivative include the following substituted forms: N-propyl allylate, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-proline isopropyl ester and N-leucine isopropyl ester. In some embodiments, R ^9C can have a structure Wherein R ^33C may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted aryl, optionally substituted aryl ( C _1-6 alkyl) and optionally substituted haloalkyl; R ^34C may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally a substituted C _3-6 cycloalkyl group, optionally substituted C ₆ aryl group, optionally substituted C ₁₀ aryl group, and optionally substituted aryl group (C _1-6 alkyl group); ^35C may be hydrogen or optionally substituted C _1-4 alkyl; or R ^34C and R ^35C may be joined together to form an optionally substituted C _3-6 cycloalkyl.

When R ^34C is substituted, R ^34C may be substituted with one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^34C can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^34C can be hydrogen. In other embodiments, R ^34C can be methyl. In some embodiments, R ^33C can be optionally substituted C _1-6 alkyl. Examples of optionally substituted C _1-6 alkyl groups include the following optionally substituted variants: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , pentyl (branched and linear) and hexyl (branched and linear). In some embodiments, R ^33C can be methyl or isopropyl. In some embodiments, R ^33C can be ethyl or neopentyl. In other embodiments, R ^33C can be an optionally substituted C _3-6 cycloalkyl. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R ^33C can be an optionally substituted cyclohexyl group. In other embodiments, R ^33C can be an optionally substituted aryl group (such as phenyl and naphthyl). In other embodiments, R ^33C can be an optionally substituted aryl (C _1-6 alkyl). In some embodiments, R ^33C can be an optionally substituted benzyl group. In some embodiments, R ^33C can be optionally substituted C _1-6 haloalkyl, such as CF ₃ . In some embodiments, R ^35C can be hydrogen. In other embodiments, R ^35C can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^35C can be methyl. In some embodiments, R ^34C and R ^35C can be joined together to form an optionally substituted C _3-6 cycloalkyl group. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the group selected for R ^34C and R ^35C , the carbon to which R ^34C and R ^{35C are} attached may be the center of the palm. In some embodiments, the carbon to which R ^34C and R ^{35C are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^34C and R ^{35C are} attached may be the (S)-pair palm center.

In some embodiments, when R ^1C is When Z ^2C can be O (oxygen). In other embodiments, when R ^1C is When Z ^2C can be S (sulfur). In some embodiments, when R ^1C is The compound of formula (I) may be an amino phosphate prodrug such as an amino aryl phosphate prodrug.

In some embodiments, R ^1C can be . In some embodiments, R ^10C and R ^11C can each be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In some embodiments, R ^10C and R ^11C are independently selected from the group consisting of alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, and lysine. , serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and Its ester derivative. In some embodiments, R ^10C and R ^11C may be substituted as follows: N-propyl propylamine, cyclohexyl N-alanine, neopentyl N-alanine, N-decylamine Isopropyl acrylate and N-leucine. In some embodiments, R ^10C and R ^11C may independently have a structure Wherein R ^36C may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted aryl, optionally substituted aryl ( C _1-6 alkyl) and optionally substituted haloalkyl; R ^37C may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally a substituted C _3-6 cycloalkyl group, optionally substituted C ₆ aryl group, optionally substituted C ₁₀ aryl group, and optionally substituted aryl group (C _1-6 alkyl group); ^38C can be hydrogen or optionally substituted C _1-4 alkyl; or R ^37C and R ^38C can be joined together to form an optionally substituted C _3-6 cycloalkyl.

When R ^37C is substituted, R ^37C may be substituted with one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^37C can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^37C can be hydrogen. In other embodiments, R ^37C can be methyl. In some embodiments, R ^36C can be optionally substituted C _1-6 alkyl. Examples of optionally substituted C _1-6 alkyl groups include the following optionally substituted variants: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , pentyl (branched and linear) and hexyl (branched and linear). In some embodiments, R ^36C can be methyl or isopropyl. In some embodiments, R ^36C can be ethyl or neopentyl. In other embodiments, R ^36C can be an optionally substituted C _3-6 cycloalkyl. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R ^36C can be an optionally substituted cyclohexyl group. In other embodiments, R ^36C can be an optionally substituted aryl group (such as phenyl and naphthyl). In other embodiments, R ^36C can be an optionally substituted aryl (C _1-6 alkyl). In some embodiments, R ^36C can be an optionally substituted benzyl group. In some embodiments, R ^36C can be optionally substituted C _1-6 haloalkyl, such as CF ₃ . In some embodiments, R ^38C can be hydrogen. In other embodiments, ^R38C can be an optionally substituted _C1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^38C can be methyl. In some embodiments, R ^37C and R ^38C can be joined together to form an optionally substituted C _3-6 cycloalkyl group. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the group selected for R ^37C and R ^38C , the carbon to which R ^37C and R ^{38C are} attached may be the center of the palm. In some embodiments, the carbon to which R ^37C and R ^{38C are} attached may be a (R)-pair palm center. In some embodiments, the carbon to which R ^37C and R ^{38C are} attached may be the (S)-pair palm center.

Suitable for and Examples of groups include the following:

In some embodiments, R ^10C and R ^11C can be the same. In some embodiments, R ^10C and R ^11C can be different.

In some embodiments, Z ^3C can be O (oxygen). In other embodiments, Z ^3C can be S (sulfur). In some embodiments, when R ^1C is The compound of formula (I) may be a prodrug phosphate prodrug.

A plurality of substituents may be present at the 4' position of the pentose ring. In some embodiments, R ^2C can be an unsubstituted C _1-4 alkyl group. Unsubstituted C _1-4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In other embodiments, R ^2C can be an unsubstituted C _2-4 alkenyl group such as a vinyl group, a propenyl group, and a butenyl group. In other embodiments, R ^2C can be an unsubstituted C _2-4 alkynyl group, such as ethynyl, propynyl, and butynyl. In other embodiments, R ^2C can be haloalkyl. Examples of haloalkyl groups are -(CH ₂ ) _1-6 halogen and -CHF ₂ . In some embodiments, the haloalkyl group can be -(CH ₂ ) _1-6 F or -(CH ₂ ) _1-6 Cl. In some embodiments, the haloalkyl group can be a fluoromethyl group. In other embodiments, R ^2C can be -CHF ₂ . In other embodiments, R ^2C can be a C _1-6 azidoalkyl group. For example, R ^2C can be an azidomethyl group, an azidoethyl group, an azidopropyl group, an azidobutyl group, an azidopentyl group or an azidohexyl group. In some embodiments, R ^2C can be a halo group. In some embodiments, R ^2C can be fluorine. In other embodiments, R ^2C can be chlorine. In other embodiments, R ^2C can be -CN.

A plurality of substituents may also be present at the 2' position of the pentose ring. In some embodiments, R ^4C can be OH. In other embodiments, R ^4C can be -OC(=O)R" ^D , wherein R" ^D can be an optionally substituted C _1-24 alkyl group. In some embodiments, R ^4C can be -OC(=O)R" ^D , wherein R" ^D can be unsubstituted C _1-4 alkyl. In other embodiments, R ^4C can be a halo group. In some embodiments, R ^4C can be F. In other embodiments, R ^4C can be Cl. In some embodiments, R ^4C can be N ₃ . In some embodiments, R ^4C can be NR" ^D1 R" ^D2 . For example, R ^4C can be NH ₂ . Other examples may be monosubstituted C _1-6 alkyl-amines or disubstituted C _1-6 alkyl-amines.

In other embodiments, R ^4C can be an optionally substituted O-linked amino acid, such as an O-linked alpha-amino acid. In some embodiments, the O-linked amino acid can have a structure Wherein R ^42C may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C ₆ aryl, optionally substituted C ₁₀ aryl and optionally substituted aryl (C _1-6 alkyl); and R ^43C can be hydrogen or optionally substituted C _1-4 An alkyl group; or R ^42C and R ^43C may be bonded together to form an optionally substituted C _3-6 cycloalkyl group.

When R ^42C is substituted, R ^42C may be substituted with one or more substituents selected from the group consisting of N-decylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^42C can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^42C can be hydrogen. In other embodiments, R ^42C can be methyl. In some embodiments, R ^43C can be hydrogen. In other embodiments, R ^43C can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^43C can be methyl. Depending on the group selected for R ^42C and R ^43C , the carbon to which R ^42C and R ^{43C are} attached may be the center of the palm. In some embodiments, the carbon to which R ^42C and R ^{43C are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^42C and R ^{43C are} attached may be the (S)-pair palm center.

Suitable for Examples include the following: , ,

In some embodiments, R ^5C can be H. In other embodiments, R ^5C can be a halo group, including F and Cl. In other embodiments, R ^5C can be optionally substituted C _1-6 alkyl. For example, R ^5C can be substituted or unsubstituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branches) Chain or linear) and hexyl (branched or linear). In some embodiments, R ^5C can be a halo substituted C _1-6 alkyl group, such as —CH ₂ F. In other embodiments, R ^5C can be an optionally substituted C _2-6 alkenyl group. In some embodiments, R ^5C can be an optionally substituted C _2-6 alkynyl group. For example, R ^5C can be an ethynyl group. In some embodiments, R ^5C can be a hydroxyl group (OH).

In some embodiments, --- may not be present such that the compound of formula (I) has the structure: . When neither -------- is present, there may be multiple groups at the 3' position. In some embodiments, R ^3C can be H. In other embodiments, R ^3C can be a halo group such as fluorine (F) or chlorine (Cl). In other embodiments, R ^3C can be OH. In some embodiments, R ^3C can be -OC(=O)R" ^C , wherein R" ^C can be an optionally substituted C _1-24 alkyl group. In some embodiments, R ^3C can be -OC(=O)R" ^C , wherein R" ^C can be unsubstituted C _1-4 alkyl. In other embodiments, R ^3C can be an optionally substituted O-linked amino acid, such as an O-linked alpha-amino acid. The optionally substituted O-linked amino acid may have a structure Wherein R ^44C may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C ₆ aryl, optionally substituted C ₁₀ aryl and optionally substituted aryl (C _1-6 alkyl); and R ^45C can be hydrogen or optionally substituted C _1-4 alkane Or R ^44C and R ^45C may be combined to form an optionally substituted C _3-6 cycloalkyl group.

When R ^44C is substituted, R ^44C may be substituted with one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted Heteroaryl, O-carboxy and amine groups. In some embodiments, R ^44C can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^44C can be hydrogen. In other embodiments, R ^44C can be methyl. In some embodiments, R ^45C can be hydrogen. In other embodiments, R ^45C can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^45A can be methyl. Depending on the group selected for R ^44C and R ^45C , the carbon to which R ^44C and R ^{45C are} attached may be the center of the palm. In some embodiments, the carbon to which R ^44C and R ^{45C are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^44C and R ^{45C are} attached may be the (S)-pair palm center.

Suitable for Examples include the following: , ,

In some embodiments, R ^3C and R ^4C can each be an oxygen atom that forms a 5-membered ring via a carbonyl linkage.

In some embodiments, R ^2C can be fluorine and R ^3C can be fluorine. In some embodiments, R ^2C can be fluorine and R ^4C can be fluorine. In some embodiments, R ^2C can be fluoro, R ^3C can be fluoro, and R ^5C can be optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl. In some embodiments, R ^2C can be fluoro, R ^4C can be fluoro, and R ^5C can be optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl. In some embodiments, R ^2C can be fluorine, R ^3C can be fluorine, and R ^4C can be OH or -OC(=O)R" ^D. In some embodiments, R ^2C can be fluorine and R ^3C can be OH or -OC(=O)R" ^C and R ^4C may be fluorine. In some embodiments, R ^4C and R ^5C can each be F. In some embodiments, R ^2C can be *-(CH ₂ ) _1-6 halogen (eg, -CH ₂ F), and R ^3C can be OH, -OC(=O)R" ^C, or optionally substituted The linked amino acid and R ^4C can be OH. In some embodiments, R ^2C can be -(CH ₂ ) _1-6 halogen (eg, -CH ₂ F), R ^3C can be OH, -OC (=O R" ^C or optionally substituted O-linked amino acid, ^R4C may be OH and ^R5C may be unsubstituted _C1-6 alkyl. In some embodiments, R ^2C can be -(CH ₂ ) _1-6 N ₃ (such as -CH ₂ N ₃ ), R ^3C can be OH, and R ^4C can be F.

In some embodiments, --- may each be a single bond such that the compound of formula (I) has the structure: . When -------- is each a single bond, R ^3C may be oxygen (O). In some embodiments, when -------- are each a single bond, R ^1D can be O ^- or OH. In other embodiments, when --- each is a single bond, R ^1D can be -O- optionally substituted C _1-6 alkyl. For example, R ^1D can be -O-unsubstituted C _1-6 alkyl.

In some embodiments, when -------- are each a single bond, R ^1D can be . In other embodiments, R ^1D can be . For example, R ^1D can be isopropoxycarbonyloxymethoxy or pentyloxymethoxy. In other embodiments, R ^1B can be . S-mercaptothioethyl (SATE) is An example of a base. In other embodiments, R ^1D can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

Examples of optionally substituted N-linked amino acids and optionally substituted N-linked amino acid ester derivatives are described herein. In some embodiments, R ^{1D can be} selected from the group consisting of alanine, aspartame, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, serine, Tyrosic acid, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and their ester derivatives. In some embodiments, R ^1D can be substituted as follows: N-propyl propyl acrylate, cyclohexyl N-alanine, neopentyl N-alanine, isopropyl N-proline Ester and isopropyl N- lysinate. In some embodiments, R ^1D can have a structure Wherein R ^10D may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted aryl, optionally substituted aryl ( C _1-6 alkyl) and optionally substituted haloalkyl; R ^11D may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally a substituted C _3-6 cycloalkyl group, optionally substituted C ₆ aryl group, optionally substituted C ₁₀ aryl group, and optionally substituted aryl group (C _1-6 alkyl group); ^12D may be hydrogen or optionally substituted C _1-4 alkyl; or R ^11D and R ^12D may be combined to form an optionally substituted C _3-6 cycloalkyl.

As described herein, R ^11D can be substituted. Examples of the substituent include one or more substituents selected from the group consisting of N-nonylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted heteroaryl, O-carboxyl And an amine group. In some embodiments, R ^11D can be an unsubstituted C _1-6 alkyl group, such as described herein. In some embodiments, R ^11D can be hydrogen. In other embodiments, R ^11D can be methyl. In some embodiments, R ^10D can be an optionally substituted C _1-6 alkyl group. In some embodiments, R ^10D can be methyl, ethyl, isopropyl or neopentyl. In other embodiments, R ^10D can be an optionally substituted C _3-6 cycloalkyl. Examples of the C _3-6 cycloalkyl group which may be optionally substituted include the following optionally substituted variants: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R ^10D can be an optionally substituted cyclohexyl group. In other embodiments, R ^10D can be an optionally substituted aryl group (such as phenyl and naphthyl). In other embodiments, R ^10D can be an optionally substituted aryl (C _1-6 alkyl) group, such as optionally substituted benzyl. In some embodiments, R ^10D can be an optionally substituted C _1-6 haloalkyl group, such as CF ₃ . In some embodiments, R ^12D can be hydrogen. In other embodiments, R ^12D can be an optionally substituted C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R ^12D can be methyl. In some embodiments, R ^11D and R ^12D can be joined together to form an optionally substituted C _3-6 cycloalkyl group. Depending on the group selected for R ^11D and R ^12D , the carbon to which R ^11D and R ^{12D are} attached may be the center of the palm. In some embodiments, the carbon to which R ^11D and R ^{12D are} attached may be a (R)-pair palm center. In other embodiments, the carbon to which R ^11D and R ^{12D are} attached may be the (S)-pair palm center.

Suitable for Examples of groups include the following: ,

In some embodiments, R ^1D can be . In some embodiments, R ^9D can be hydrogen. In other embodiments, R ^9D can be an optionally substituted C _1-24 alkyl group. In other embodiments, R ^9D can be an optionally substituted aryl group, such as optionally substituted phenyl. In some embodiments, R ^9D can be an optionally substituted C _1-6 alkyl group. In some embodiments, R ^9D can be an unsubstituted C _1-6 alkyl group. In some embodiments, k can be 3. In other embodiments, k can be four. In other embodiments, k can be 5.

A plurality of substituents may also be present at the 1' position of the pentose ring. In some embodiments, R ^C can be hydrogen. In some embodiments, R ^C can be deuterium. In other embodiments, R ^C can be an unsubstituted C _1-3 alkyl group (such as methyl, ethyl, n-propyl, and isopropyl). In other embodiments, R ^C can be an unsubstituted C _2-4 alkenyl group (eg, ethenyl, propenyl (branched or linear) and butenyl (branched or linear)). In some embodiments, R ^C can be an unsubstituted C _2-3 alkynyl group (such as ethynyl and propynyl (branched or linear)). In other embodiments, R ^C can be an unsubstituted cyano group.

In some embodiments, Z ^1D can be oxygen (O). In other embodiments, Z ^1D can be S (sulfur).

A plurality of optionally substituted heterocyclic bases can be attached to the pentose ring. In some embodiments, one or more amine and/or amine groups of optionally substituted heterocyclic bases may be protected by a protecting group. For example, an amine group can be protected by converting an amine and/or an amine group to a guanamine or a urethane. In some embodiments, optionally substituted heterocyclic bases or optionally substituted heterocyclic bases can include increasing the solubility of the compound (eg, -(CH ₂ ) _1-2 -OP(=O)(OW ^2C ) ₂ ). In some embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having one or more protected amine groups can have one of the following structures: Wherein: R ^AA2 may be selected from the group consisting of hydrogen, halogen and NHR ^JJ2 , wherein R ^JJ2 may be selected from hydrogen, -C(=O)R ^KK2 and -C(=O)OR ^LL2 ; R ^BB2 may be halogen or NHR ^WW2 , wherein R ^WW2 may be selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _3-8 cycloalkyl, -C(=O) R ^MM2 and -C(=O)OR ^NN2 ; R ^CC2 may be hydrogen or NHR ^OO2 , wherein R ^OO2 may be selected from hydrogen, -C(=O)R ^PP2 and -C(=O)OR ^QQ2 ; R ^DD2 may Selected from hydrogen, deuterium, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; R ^{EE 2} may be selected from hydrogen , hydroxy, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, -C(=O)R ^RR2 and -C(=O)OR ^SS2 ; R ^FF2 optional From hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; Y ⁴ and Y ⁵ may independently N (nitrogen) or CR ^II2 , wherein R ^II2 may be selected from hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _{2 - 6} alkynyl; W ² can be NH, -NCH ₂ -OC (= O)CH(NH ₂ )-CH(CH ₃ ) ₂ or -(CH ₂ ) _1-2 -OP(=O)(OW ^2C ) ₂ , wherein W ^2C may be selected from the absence of hydrogen and optionally substituted C _1-6 alkyl; R ^GG2 may be optionally substituted C _1-6 alkyl; R ^{HH 2} may be hydrogen or NHR ^TT2 , wherein R ^TT2 may be independently selected from hydrogen, -C(=O)R ^UU2 And -C(=O)OR ^VV2 ; and R ^KK2 , R ^LL2 , R ^MM2 , R ^NN2 , R ^PP2 , R ^QQ2 , R ^RR2 , R ^SS2 , R ^UU2 and R ^VV2 may be independently selected from hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, heteroaryl, heterocyclic, aromatic a (C _1-6 alkyl) group, a heteroaryl group (C _1-6 alkyl group) and a heterocyclic group (C _1-6 alkyl group). In some embodiments, the structures shown above can be modified by replacing one or more hydrogens with a substituent selected from the list of substituents provided in the definition of "substituted". Be appreciated by those skilled in the art is not present when W ^2C, an oxygen atom having a negative charge associated. In some embodiments, a substituent on a base can result in the formation of a salt of a compound of formula (II).

In some embodiments, B ^1C can be an optionally substituted purine base. In other embodiments, B ^1C can be an optionally substituted pyrimidine base. In some embodiments, B ^1C can be . In other embodiments, B ^1C can be . In other embodiments, B ^1C can be , such as . In other embodiments, B ^1C can be Wherein W ² may be -NCH ₂ -OC(=O)CH(NH ₂ )-CH(CH ₃ ) ₂ or -(CH ₂ ) _1-2 -OP(=O)(OW ^2C ) ₂ . In some embodiments, B ^1C can be ,E.g or . In other embodiments, R ^DD2 can be hydrogen. In other embodiments, B ^1C can be . In some embodiments, R ^BB2 can be NH ₂ . In other embodiments, R ^BB2 can be NHR ^WW2 , where R ^WW2 can be -C(=O)R ^MM2 or -C(=O)OR ^NN2 . In other embodiments, B ^1C can be . In some embodiments, B ^1C can be .

In some embodiments, when R ^2C is halo (such as fluorine); --- is absent; Z ² is absent; O ² is OR ^1C ; B ^1C is selected from the group consisting of Replace it as appropriate Replace it as appropriate Replace it as appropriate Replace it as appropriate And replaced by circumstances Wherein R ^a2 is optionally substituted C _1-6 alkyl or optionally substituted C _3-6 cycloalkyl, and R ^a3 and R ^a4 are independently selected from hydrogen, unsubstituted C _1-6 An alkyl or unsubstituted C _3-6 alkenyl group, an unsubstituted C _3-6 alkynyl group, and an unsubstituted C _3-6 cycloalkyl group, R ^a5 is NHR ^a8 , and R ^a6 is hydrogen, halogen Or NHR ^a9 ; R ^a7 is NHR ^a10 ; R ^a8 is selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 alkenyl, optionally substituted C _3-6 Cycloalkyl, -C(=O)R ^a11 and -C(=O)OR ^a12 ; R ^a9 is selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 Alkenyl, optionally substituted C _3-6 cycloalkyl, -C(=O)R ^a13 and -C(=O)OR ^a14 ; R ^a10 is selected from hydrogen, optionally substituted C _1-6 Alkyl, optionally substituted C _3-6 alkenyl, optionally substituted C _3-6 cycloalkyl, -C(=O)R ^a15 and -C(=O)OR ^a16 ; X ^a1 is N Or -CR ^a17 ; R ^a17 is selected from the group consisting of hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; ^{R a11, R a12, R a13} , R a14, R a15 , and R ^a16 independently based Is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, heteroaryl, When a heterocyclic group, an aryl group (C _1-6 alkyl group), a heteroaryl group (C _1-6 alkyl group), and a heterocyclic group (C _1-6 alkyl group); then R ^3C is selected from H, halo group And optionally substituted O-linked amino acid; and R ^4C is selected from the group consisting of OH, halo, N ₃ , -OC(=O)R" ^D , optionally substituted O-linked amino acid and NR " ^D1 R"^D2; or R ^4C is an optionally substituted O-linked amino acid; and R ^3C is selected from H, halo, OH, -OC(=O)R" ^C and optionally substituted O-bonded amino acid; or R ^1C is Where R ^6C and R ^{7C are} independently Where h is 1, 2 or 3, or Or R ^1C is Wherein R ^6C and R ^7C are taken together to form a moiety selected from the group consisting of: And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6C and R ^7C form a six to ten member ring system. In some embodiments, when R ^2C is halo (such as fluorine); --- each is a single bond; then R ^4C is -OC(=O)R" ^D or optionally substituted O linkages amino acids. in some embodiments, when R ^2C is non-substituted C _1-4 alkyl, unsubstituted alkenyl group of C _2-4, unsubstituted of C _2-4 alkynyl group, -(CH ₂ ) _1-6 halogen or -(CH ₂ ) _1-6 N ₃ ;-------- are absent; Z ² is absent; O ² is OR ^1C ; R ^3C is OH, - OC(=O)R" ^C or an optionally substituted O-linked amino acid; and R ^4C is a halogen group; then R ^5C is selected from optionally substituted C _1-6 alkyl, as the case may be Substituted C _2-6 alkenyl and optionally substituted C _2-6 alkynyl. In some embodiments, when R ^2C is non-substituted C _1-4 alkyl, unsubstituted alkenyl group of C _2-4, unsubstituted of C _2-4 alkynyl, - (CH _{2) 1- 6} halogen, -(CH ₂ ) _1-6 N ₃ ;-------- are absent; Z ² is absent; O ² is OR ^1C ; R ^4C is halo; and R ^5C is H or halogen Base time; then R ^3C is H or a halogen group. In some embodiments, when R ^2C is non-substituted C _1-4 alkyl, unsubstituted alkenyl group of C _2-4, unsubstituted of C _2-4 alkynyl, - (CH _{2) 1- 6} halogen or -(CH ₂ ) _1-6 N ₃ ;-------- are absent; Z ² is absent; O ² is OR ^1C ; R ^3C is OH, -OC(=O)R" ^C or an optionally substituted O-linked amino acid; R ^4C is a halogen group; R ^5C is H or a halogen group; and R ^1C is At least one of R ^6C and R ^7C is Wherein R ^{21C is} independently selected from optionally substituted -O-heteroaryl and optionally substituted -O-monocyclic heterocyclyl; or at least one of R ^6C and R ^7C is Where h is 1, 2 or 3; or at least one of R ^6C and R ^7C is Wherein h is 0 and R ^24C is optionally substituted -O-heteroaryl or optionally substituted -O-monocyclic heterocyclyl. In some embodiments, when R ^2C is non-substituted C _1-4 alkyl, unsubstituted alkenyl group of C _2-4, unsubstituted of C _2-4 alkynyl, - (CH _{2) 1- 6} halogen or -(CH ₂ ) _1-6 N ₃ ;-------- are absent; Z ² is absent; O ² is OR ^1C ; R ^3C is OH, -OC(=O)R" ^C or an optionally substituted O-linked amino acid; R ^4C is a halogen group; R ^5C is H or a halogen group; and R ^1C is Time; then R ^8C is Wherein R ^{21C is} independently selected from optionally substituted -O-heteroaryl and optionally substituted -O-monocyclic heterocyclyl; or R ^8C is Where h is 1, 2 or 3; or R ^8C is Wherein h is 0 and R ^24C is optionally substituted -O-heteroaryl, optionally substituted -O-monocyclic heterocyclyl or . In some embodiments, when -------- is absent; Z ² is absent; O ² is OH; R ^2C is methyl; R ^3C is OH; then R ^4C is halo, -OC (=O) R" ^D or optionally substituted O-linked amino acid. In some embodiments, when -------- is absent; Z ² is absent; O ² is OR ^1C ; R ^2C is halo (eg F); R ^3C is OH or -OC(=O)R"^C; R ^4C is halo (eg F); and R ^5C is methyl, ethyl or vinyl; R ^1C cannot be selected from H, and , wherein R ^8C is an unsubstituted aryl group; R ^9C is And Z ^2C is oxygen. In some embodiments, when R ^2C is halo (such as F), R ^3C is OH, R ^4C is NH ₂ , and R ^4C is unsubstituted C _1-6 alkyl (such as CH ₃ ) and --- If neither - is present, then R ^1C cannot be H. In some embodiments, when R ^1C is or ;R ^6C is R ^8C is an optionally substituted aryl group, and R ^9C is an optionally substituted N-linked amino acid or an optionally substituted N-bonded amino acid ester; then R ^5C is H, a halogen group, Optionally substituted C _1-6 alkyl or optionally substituted C _2-6 alkenyl. In some embodiments, R ^{1C is} not hydrogen (H), such as when R ^3C is halo (such as fluorine) and R ^4C is OH. In some embodiments, R ^{1C is} not Where Z ^1C is O and R ^6C is For example, when R ^4C is a halogen group such as fluorine and R ^3C is OH. In some embodiments, R ^{2C is} not hydrogen (H). In some embodiments, R ^{2C is} not fluorine (F). In some embodiments, R ^{2C is} not -CN. In some embodiments, R ^{2C is} not -CHF ₂ . In some embodiments, R ^{5C is} not hydrogen or halo. In some embodiments, R ^{4C is} not halo. In some embodiments, R ^{4C is} not fluorine (F). In some embodiments, R ^{4C is} not chlorine (Cl). In some embodiments, R ^{2C is} not an unsubstituted C _1-4 alkyl group. In some embodiments, R ^{2C is} not an unsubstituted C _2-4 alkenyl group. In some embodiments, R ^{2C is} not an unsubstituted C _2-4 alkynyl group. In some embodiments, R ^{2C is} not -(CH ₂ ) _1-6 halogen. In some embodiments, R ^{2C is} not -(CH ₂ ) _1-6 N ₃ . In some embodiments, R ^{2C is} not -(CH ₂ ) _1-6 NH ₂ . In some embodiments, R ^{2C is} not halogen (eg, fluorine). In some embodiments, when R ^5C is fluorine, R ^{4C is} not hydrogen. In some embodiments, R ^{5C is} not a C _2-6 alkynyl group that is optionally substituted. In some embodiments, R ^{5C is} not selected from optionally substituted C _2-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl. In some embodiments, when R ^5C is optionally substituted C _2-6 alkynyl, R ^{2C is} not hydrogen (H). In some embodiments, R ^{5C is} not -OH. In some embodiments, R ^{4C is} not hydrogen (H). In some embodiments, R ^{4A is} not N ₃ . In some embodiments, R ^{4A is} not NH ₂ . In some embodiments, R ^{6C is} not an optionally substituted aryl group. In some embodiments, R ^{6C is} not an unsubstituted aryl group. In some embodiments, R ^{9C is} not isopropyl N-alanine. In some embodiments, R ^{5C is} not optionally substituted C _1-6 alkyl. For example, R ^{5C is} not an unsubstituted C _1-6 alkyl group such as a methyl group. In some embodiments, B ^{1C is} not an optionally substituted uracil, such as a halo substituted uracil. In some embodiments, when R ^1C is hydrogen, optionally substituted thiol, , where R ^6C can be ,or Wherein R ^8C is unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl and R ^9C is optionally substituted N-linked amino acid or optionally substituted N-bonded amine group Acid ester; R ^2C is fluorine, R ^3C is OH or -C(=O)-unsubstituted or substituted phenyl; R ^4C is fluorine; and R ^5C is C _1-4 alkyl (such as methyl) When B ^{1C is} not a pyrimidine base that is optionally substituted, such as or . In some embodiments, when R ^1C is ^Where R ^2C is H, R ^3C is OH and R ^4C is OH or halogen (such as F), then R ^{5C is} not optionally substituted C _1-6 alkyl, optionally substituted C _2-6 olefin A C _2-6 alkynyl group substituted or optionally substituted.

Examples of the compound of the formula (I) and/or (II) or a pharmaceutically acceptable salt thereof include, but are not limited to: , or a pharmaceutically acceptable salt thereof.

Additional examples of a compound of formula (I) and/or (II) or a pharmaceutically acceptable salt thereof include, but are not limited to: , or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, may be selected from the group consisting of: and , or a pharmaceutically acceptable salt thereof. (section H)

In some embodiments, the compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, may be selected from the group consisting of: , or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) and / or (II), or a pharmaceutically acceptable salt thereof, may be selected from the group consisting of: and , or a pharmaceutically acceptable salt thereof. (paragraph B)

In some embodiments, the compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, is not selected from: , or a pharmaceutically acceptable salt thereof. (paragraph C)

In some embodiments, the compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, is not selected from: , or a pharmaceutically acceptable salt thereof. (paragraph D)

In some embodiments, the compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, is not selected from: and , or a pharmaceutically acceptable salt thereof. (paragraph E)

In some embodiments, the compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, is not selected from: and , or a pharmaceutically acceptable salt thereof. (section F)

In some embodiments, the compound of Formula (I) and/or (II), or a pharmaceutically acceptable salt thereof, is not selected from: , or a pharmaceutically acceptable salt thereof. (section G)

In some embodiments, when the virus is HCV, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not selected from the compounds of paragraphs H to G. In some embodiments, when the virus is HCV, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not selected from the compounds of paragraphs C to G. In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is not selected from the compounds of paragraphs H to G. In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is not selected from the compounds of paragraphs C to G. In some embodiments, the compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof is not WO 2013/092481 (filed on December 17, 2012), U.S. 2013/0164261 (2012) Application on December 20th), WO 2014/100505 (application on December 19, 2013), WO 2013/096679 (application on December 20, 2012), WO 2013/142525 (application on March 19, 2013) or the United States A compound or a pharmaceutically acceptable salt thereof in the application No. 14/312,990, filed on Jun. 24, 2014.

Pharmaceutical composition

Some embodiments described herein relate to a pharmaceutical composition which may comprise an effective amount of one or more of the compounds described herein (eg, a compound of formula (I) and / or (II)) or a pharmaceutically acceptable compound thereof Salt, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. In some embodiments, a pharmaceutical composition can include a single diastereomer of a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof (eg, a single diastereomer to The total concentration of other diastereomers is present in the pharmaceutical composition at a concentration greater than 99%. In other embodiments, the pharmaceutical compositions may comprise a mixture of diastereomers of a compound of formula (I) and / or (II) or a pharmaceutically acceptable salt thereof. For example, a pharmaceutical composition can include a concentration >50% compared to the total concentration of other diastereomers, 60%, 70%, 80%, 90%, 95% or 98% of one diastereomer. In some embodiments, a pharmaceutical composition comprises a 1:1 mixture of two diastereomers of a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof.

The term "pharmaceutical composition" refers to a mixture of one or more of the compounds disclosed herein with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate the administration of a compound to a living organism. The pharmaceutical composition can also be obtained by reacting a compound with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. . Pharmaceutical compositions will generally be suitable for a particular intended route of administration. The pharmaceutical compositions are suitable for human and/or veterinary applications.

The term "physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.

As used herein, "carrier" refers to a compound that promotes the incorporation of a compound into a cell or tissue. Things. By way of example and not limitation, dimethyl hydrazine (DMSO) is a commonly used carrier that facilitates uptake of various organic compounds into cells or tissues of an individual.

As used herein, "diluent" refers to a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the volume of an effective drug that is too small for the block to be manufactured and/or administered. It may also be a liquid to dissolve the drug to be administered by injection, ingestion or inhalation. A common diluent form in the art is a buffered aqueous solution such as, but not limited to, a phosphate buffered physiological saline that mimics the composition of human blood.

As used herein, "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, a volume, consistency, stability, adhesion, lubrication, disintegration ability, and the like, to the composition. "Diluent" is a type of excipient.

The pharmaceutical compositions described herein can be administered to human patients by themselves or in the form of a pharmaceutical composition in admixture with other active ingredients (e.g., in combination therapy) or carriers, diluents, excipients, or combinations thereof. Appropriate formulations will depend on the chosen route of administration. Techniques for formulating and administering the compounds described herein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein can be made in a manner known per se, for example by means of conventional mixing, dissolving, granulating, dragee, water milling, emulsifying, encapsulating, embedding or ingot making processes. In addition, the active ingredient is included in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided in the form of a pharmaceutically compatible salt of the opposite ion.

A variety of techniques for administering compounds in the art include, but are not limited to, oral, rectal, topical, aerosol, injection, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, Intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injections.

The compound may also be administered in a local rather than systemic manner, for example, by direct injection of the compound into the affected area, usually in the form of a depot or sustained release formulation. In addition, it can be administered in a targeted drug delivery system (eg, in liposomes coated with tissue-specific antibodies) Compound. Liposomes will target the organ and be selectively absorbed by the organ.

Where necessary, the compositions may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing active ingredient. The package may, for example, comprise a metal or plastic foil, such as a blister pack. The package or dispenser device can be accompanied by instructions for administration. The package or dispenser may also be accompanied by a precaution associated with the container in the form of a government agency that regulates the manufacture, use or sale of the pharmaceutical product, which presupposes that the agency approves the pharmaceutical form for human or veterinary administration. . Such considerations may be, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions which can include a compound described herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and labeled for treatment of the indicated condition.

synthesis

Compounds of formula (I), compounds of formula (II), and those described herein can be prepared in a variety of ways. Some examples of the general synthetic routes of the compounds of formula (I), the compounds of formula (II) and the starting materials for the synthesis of the compounds of formula (I) and (II) are shown in Schemes 1, 2, 3 and 4 and are herein Describe it. The illustrations shown and described herein are merely illustrative and are not intended to be construed as limiting the scope of the claims. Those skilled in the art will be able to recognize modifications and alternatives to the disclosed compositions based on the disclosure herein; all such modifications and alternatives are within the scope of the patent application.

Compounds of formula (I) and (II) can be prepared using a variety of methods known to those skilled in the art. Examples of methods are shown in Schemes 1, 2, 3 and 4. Suitable phosphorus-containing precursors are commercially available or can be prepared by synthetic methods known to those skilled in the art. Examples of general structures for phosphorus-containing precursors are shown in Schemes 1, 2, 3, and 4, and include chlorophosphates and thiochlorophosphates. Suitable chlorophosphates and thiochlorophosphates are commercially available and/or can be prepared synthetically.

Process 1

As shown in Scheme 1, the compounds of formula (I) and (II) wherein the 4' position is haloalkyl can be prepared from nucleosides (e.g., nucleosides of formula (A)). In Scheme 1, R ^a , R ^3a , R ^4a , R ^5a and B ^1a may be as defined herein for R ^A /R ^C , R ^3A /R ^3C , R ^4A / of formula (I) and (II), respectively. R ^4C , R ^5A /R ^5C and B ^1A /B ^{1C are the} same, and PG ¹ is a suitable protecting group. The hydroxyalkyl group can be formed at the 4' position of the pentose ring using suitable conditions known to those skilled in the art. Examples of suitable conditions for the formation of the hydroxyalkyl group include the use of 2-dioxyiodobenzoic acid (IBX) aqueous formaldehyde solution and sodium borohydride. The compound of formula (B) can be converted to a haloalkyl group using a suitable reagent, for example, using imidazole, triphenylphosphine, and iodine to convert to iodide; using diethylamine trifluoride trifluoride (DAST) to convert to fluoride; or Triphenylphosphine and carbon tetrachloride (DCE) are converted to chloride.

Process 2

The compounds of formula (I) and (II) wherein R ^2A /R ^2C is C _1-6 azidoalkyl can be prepared from nucleosides (e.g., nucleosides of formula (A)). In Scheme 2, R ^a , R ^3a , R ^4a , R ^5a and B ^1a may be as defined herein for R ^A /R ^C , R ^3A /R ^3C , R ^4A / of formula (I) and (II), respectively. R ^4C , R ^5A /R ^5C and B ^1A /B ^{1C are the} same, PG ² may be a suitable protecting group and LG ² may be a suitable leaving group. The 5' position of the nucleoside can be oxidized to the aldehyde using methods known to those skilled in the art. Suitable oxidizing conditions include, but are not limited to, Moffatt oxidation, Swern oxidation, and Corey-Kim oxidation; and suitable oxidants include, but are not limited to, Days -Dess-Martin periodinane, IBX (2-diiodoiodobenzoic acid), TPAP/NMO (tetrapropylammonium perrhenate/N-methylmorpholine N-oxide), sulphur oxidant , PCC (pyridinium chlorochromate) and / or PDC (pyridinium dichromate), sodium periodate, Collin's reagent, ammonium cerium nitrate CAN, water containing Na ₂ Cr ₂ O ₇ , hydrazine Ag ₂ CO ₃ on the algae soil, hot HNO ₃ in the aqueous solution of ethylene glycol dimethyl ether, O ₂ -pyridine CuCl, Pb(OAc) ₄ -pyridine and benzamidine peroxide - NiBr ₂ . A hydroxymethyl group can be added to the 4' position of the pentose ring while the aldehyde is reduced to an alcohol. The hydroxymethyl group can be added by condensation using formaldehyde and a base such as sodium hydroxide. After the addition of the hydroxymethyl group, the intermediate compound can be reduced with a 4'-hydroxymethyl group using a reducing agent. Examples of suitable reducing agents include (but are not limited to) NaBH ₄ and LiAlH _4. The hydrogen which is attached to the 4' position of the hydroxymethyl group can be formed to form a suitable leaving group (such as a triflate), and the oxygen attached to the 5' position can be protected with a suitable protecting group (for example, with a base, B ^1a). Or individual protection groups are cyclized). The leaving group can be replaced with an azide group using a metal azide reagent such as sodium azide. The C _1-6 azidoalkyl group at the 4' position can be reduced to a C _1-6 aminoalkyl group. A variety of reducing agents/conditions known to those skilled in the art can be employed. For example, the azide group can be hydrogenated (eg, H ₂ -Pd/C or HCO ₂ NH ₄ -Pd/C), Staudinger Reaction, NaBH ₄ /CoCl ₂ ̇6 H ₂ O, Reduction of Fe/NH ₄ Cl or Zn/NH ₄ Cl to an amine group.

Process 4

Compounds of formula (I) and (II) having a phosphorus-containing group attached to the 5' position of the pentose ring can be prepared using a variety of methods known to those skilled in the art. Examples of methods are shown in Schemes 3 and 4. In Schemes 3 and 4, R ^a , R ^2a , R ^3a , R ^4a , R ^5a and B ^1a may be used herein for R ^A /R ^C , R ^2A /R as described for formulas (I) and (II), respectively. ^2C , R ^3A /R ^3C , R ^4A /R ^4C , R ^5A /R ^5C and B ^1A /B ^{1C are the} same. The phosphorus-containing precursor can be coupled to a nucleoside, such as a compound of formula (B). After coupling with the phosphorus-containing precursor, any leaving groups can be cleaved (such as hydrolyzed) under suitable conditions. Other phosphorus-containing groups can be added using methods known to those skilled in the art (e.g., using pyrophosphate). If desired, one or more bases can be used during the addition of each phosphorus-containing group. Examples of suitable bases are described herein.

In some embodiments, the alkoxide can be produced from a compound of formula (C) using an organometallic reagent such as a Grignard reagent. The alkoxide can be coupled to a phosphorus-containing precursor. Suitable Grenner reagents are known to those skilled in the art and include, but are not limited to, alkyl magnesium chloride and alkyl magnesium bromide. In some embodiments, a suitable base can be used. Examples of suitable bases include, but are not limited to, amine bases such as alkylamines (including mono-, di- and tri-alkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g., trimethylpyridine), and Imformed imidazole (eg N-methylimidazole). Alternatively, the phosphorus-containing precursor can be added to the nucleoside and form a phosphite. The phosphite can be oxidized to a phosphate ester using conditions known to those skilled in the art. Suitable conditions include, but are not limited to, m-chloroperoxybenzoic acid (MCPBA) and iodine (as oxidant) and water (as oxygen donor).

When Z ^1A /Z ^1C , Z ^2A /Z ^2C or Z ^3A /Z ^3C of the compounds of formula (I) and (II) are sulfur, the sulfur can be added in a variety of ways known to those skilled in the art. In some embodiments, the sulfur can be part of a phosphorus-containing precursor, such as , , or . Alternatively, sulfur can be added using a vulcanizing agent. Suitable vulcanizing agents are known to those skilled in the art and include, but are not limited to, elemental sulfur, Lawesson's reagent, cyclooctasulfur, 3H-1,2-benzodithiophene-3- Keto-1,1-dioxide (Beaucage's reagent), 3-((N,N-dimethylaminomethylene)amino)-3H-1,2,4-di Thiazol-5-thione (DDTT) and bis(3-triethoxydecyl)propyl-tetrasulfide (TEST).

As described herein, in some embodiments, R ^3A and R ^4A and/or R ^3C and R ^4C can each be an oxygen atom wherein the oxygen atoms are bonded together via a carbonyl group. The -OC(=O)-O- group can be formed using methods known to those skilled in the art. For example, a compound of formula (I) wherein both R ³ and R ⁴ are hydroxy can be treated with 1,1 '-carbonyldiimidazole (CDI).

In some embodiments, the 2'-position and/or the 3'-position of the pentose ring may have, for example, an optionally substituted -O-thiol group attached to -OC(=O)R" ^A . The -O-thiol group can be formed at the 2' and/or 3' positions using a variety of methods known to those skilled in the art. For example, the 2' position and the 3' position are each linked to a hydroxyl group of formula (I) and The compound (II) can be treated with an alkyl anhydride (for example, acetic anhydride and propionic anhydride) or an alkyl acid chloride (for example, ethyl chloroformate). If necessary, a catalyst can be used to promote the reaction. An example of a suitable catalyst is 4-two. Methylaminopyridine (DMAP). Alternatively, the -O-fluorenyl group may be substituted at 2' by reacting an alkyl acid such as acetic acid and propionic acid in the presence of a carbodiimide or a coupling agent. Formed at the 3' position. Examples of carbodiimides include, but are not limited to, N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) And 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

To reduce by-product formation, one or more groups attached to the pentose ring may be protected by one or more suitable protecting groups and/or any -NH and/or NH ₂ groups present on B ^1a may be used. Multiple suitable for protection base protection. For example, if the 2' position and/or the 3' position is a hydroxyl group, the hydroxyl group can be protected by a suitable protecting group such as a triarylmethyl group and/or a decyl group. Examples of triarylmethyl groups include, but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4, 4' , 4"-trimethoxytrityl (TMTr), 4,4',4"-para-(benzylideneoxy)trityl (TBTr), 4,4',4"-para ( 4,5-Dichloro-phenanthrylene imino)trityl (CPTr), 4,4',4"-e(epipropoxy)trityl (TLTr), p-anisyl- 1-naphthylphenylmethyl, di-anisyl-1-naphthylmethyl, p-tolyldiphenylmethyl, 3-(imidazolylmethyl)-4,4'-dimethoxytriphenyl Methyl, 9-phenyldibenzopyran-9-yl (Pixyl), 9-(p-methoxyphenyl)dibenzopyran-9-yl (Mox), 4-decyloxytriphenyl , 4-hexadecyltrityl, 4,4'-bis(octadecyl)trityl, 9-(4-octadecyloxy)dibenzopyran-9-yl 1,1'-bis-(4-methoxyphenyl)-1'-mercaptomethyl, 4,4',4"-para-(t-butylphenyl)methyl (TTTr) and 4,4'-Di-3,5-hexadienyloxytrityl. Examples described herein as suitable for decyl groups and include trimethyl decyl (TMS), tert-butyl dimethyl decyl (TBDMS) ), triisopropyl decyl (TIPS), third Diphenyl silicon group (TBDPS), three - isopropyl-alkoxymethyl group and silicon [2- (trimethyl silicon alkyl)) ethoxy] methyl, or, R ^3A and / or R ^4A may be by A single non-pivoling or palmitic protecting group is protected, for example, by the formation of orthoesters, cyclic acetals or cyclic ketals. Suitable orthoesters include methoxymethylene acetal, ethoxylated Methyl acetal, 2-oxocyclopentyl orthoester, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester , methylene orthoester, benzoate orthoester 1,2-dimethoxyethyl orthoester and α-methoxybenzylidene acid ester; suitable cyclic acetal including methylene Acetal, ethylene acetal, tert-butylmethylene acetal, 3-(benzyloxy)propyl acetal, benzylidene acetal, 3,4-dimethoxybenzamide Alkyl acetal and p-ethoxy benzyl acetal acetal; and suitable cyclic ketals include 1-tert-butylethylene ketal, 1-phenylethyl ketal, isopropylidene Ketone, cyclopentylene ketal, cyclohexylene ketal, cycloheptyl ketal, and 1-(4-methoxyphenyl)ethylene ketal.

Instance

The other embodiments are further disclosed in the following examples, which are not intended to limit the scope of the claims.

Example 1

To a solution of 1-1 (100.0 g, 378.7 mmol) in EtOAc (EtOAc) The solution was stirred at room temperature for 15 hours. MeOH (300 mL) was added and the mixture was concentrated to dryness. The residue was dissolved in EA and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in DCM (500 mL). To this solution was added imidazole (44.3 g, 650.4 mmol) and TBSCl (91.9 g, 609.8 mmol). The mixture was stirred at room temperature for 14 hours. Solution was washed with NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, and concentrated to give a light yellow solid of the crude product. The crude product (236.4 g, 347.6 mmol) was dissolved in aq. The mixture was stirred at room temperature for 15 hours. The mixture was diluted with EA, and washed with NaHCO ₃ solution and brine. The organic layer was dried over Na ₂ SO _4, and chromatographed on silica gel column (with the DCM 1-2% MeOH) on to afford a light yellow solid of 1-2 (131.2g, 91.9%). ESI-MS: m/z 802 [M+H] ⁺ .

To 1-2 (131.2g, 346.9mmol) in anhydrous CH in the IBX solution was added _{3 CN (1200mL) (121.2g,} 432.8mmol) at room temperature. The mixture was refluxed for 3 hours and then cooled to 0 °C. The precipitate was filtered, and the filtrate was evaporated to ethylamine. The aldehyde was dissolved in 1,4-dioxane (1000 mL). 37% CH ₂ O (81.1 mL, 1.35 mmol) and 2M aqueous NaOH (253.8 mL, 50. The mixture was stirred at room temperature for 2 hours, then neutralized with AcOH to pH = 7. EtOH (400 mL) and NaBH ₄ (51.2 g, 1.35 mol) were added to the solution. The mixture was stirred for 30 minutes at room temperature, saturated aqueous NH ₄ Cl The reaction was quenched. The mixture was extracted with EA. The organic layer was dried over Na ₂ SO ₄ and concentrated. By silica gel column chromatography (1-3% MeOH containing of DCM) and the residue was purified to obtain a white solid of 1-3 (51.4g, 38.9%).

Pyridine (80 mL) and DMTrCl (49.1 g, 144.7 mmol) were added to a solution of 1-3 (51.4 g, 125.9 mmol) in anhydrous DCM (400 mL). The reaction was stirred at rt for 14 h then EtOAc (30 mL). The solvent was removed and the residue was purified EtOAcjjjjjjjj The intermediate (57.4g, 82.8mmol) was dissolved in CH ₂ Cl ₂ (400mL), and imidazole (8.4g, 124.2mmol), TBDPSCl ( 34.1g, 124.2mmol). The mixture was stirred at room temperature for 14 hours. The precipitate was filtered off, and the filtrate was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed to give a white solid (yield: 72.45 g). The residue was dissolved in 80% aqueous HOAc (400 mL). The mixture was stirred at room temperature for 15 hours. The mixture was diluted with EA, and washed with NaHCO ₃ solution and brine. The organic layer was dried over Na ₂ SO _4, and by silica gel column chromatography (1-2% MeOH containing of DCM) to afford a white solid of 1-4 (37.6g, 84.2%).

To a solution of 1-4 (700 mg, 1.09 mmol) in anhydrous dichloromethane was added <RTI ID=0.0>>> The mixture was stirred at room temperature for 30 minutes. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate and sodium thiosulfate and extracted with EtOAc. The organic layer was concentrated to give a crude aldehyde which was used in the next step without purification. At _{0 ℃, MePPh 3 Br (3.88g} , 10.87mmol) in anhydrous THF in the THF solution was treated with a solution of t-BuOK (9.81mL, 9.81mmol) . The mixture was allowed to warm to room temperature for 1 hour. After cooling to 0 °C for 1 hour, a solution of aldehyde (700 mg, 1.09 mmol) in THF was added. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was purified by column chromatography to afford 1-5 (167 mg, 30%).

Pd/C (200 mg) was added to a solution of 1-5 (450 mg, 0.69 mmol) in MeOH (10 mL). The reaction mixture was stirred under H ₂ (balloon) for 1 hour at room temperature. The mixture was then filtered and the filtrate was concentrated to give a white solid of the crude product 1-6 (440mg, 97.1%).

A solution of 1-6 (317 mg, 0.49 mmol), TPSCl (373 mg, 1.23 mmol), DMAP (150 mg, 1.23 mmol) and TEA (124 mg, 1.23 mmol) in anhydrous MeCN was stirred overnight. The reaction was quenched with NH ₃ ˙H ₂ O, followed by stirring at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography to afford 1-7 (200mg, 63%).

(, 0.44mmol 280mg) in MeOH was added a solution of 1-7 (10mL) in a solution of _{NH 4 F (1.0g, 27.0mmol)} . The mixture was refluxed for 12 hours. The mixture was filtered and the filtrate was concentrated. In the silica gel column (10% MeOH in the DCM) is obtained residue was purified as a white solid of compound 1 (81mg, 63.3%). ESI-MS: m/z 291.8 [M+H] ⁺ .

Example 2

NaH (170 mg, 4.24 mmol, 60% purity) was added to a solution of 2-1 (2.5 g, 4.04 mmol) in DMF. The mixture was stirred at room temperature for 3 hours. NaI (6.1 g, 40.4 mmol) was added at room temperature and stirred for 3 hours. The reaction was diluted with water and extracted with EA. The organic layer was dried over anhydrous Na ₂ SO _4, and concentrated to obtain a low pressure as a yellow solid of 2-2 (1.7g, 94%).

A solution of 2-2 (1.7 g, 3.81 mmol) in THF (5 mL). The solution was stirred at room temperature for 2 hours. The mixture was adjusted to pH = 7 and concentrated under reduced pressure. The mixture was partitioned between DCM and water. The DCM layer was dried in vacuo to afford 2-3 (1.

In the solution was added NH ₄ COOH (650mg, 7.75mmol) and Pd / C (120mg) to 2-3 (1.2g, 2.58mmol) in EtOH (20mL). The mixture was stirred for 1.5 hours under H ₂ (30psi) at room temperature. The suspension was filtered and the filtrate was concentrated at low pressure. On silica gel column (containing 0.5% TEA and 1% MeOH of DCM) obtained residue was purified 2-4 (545mg, 62%). ESI-MS: m/z 361.2 [M+23] ⁺ .

Compound 2-4 was dissolved in 80% aqueous HCOOH (20 mL) and kept at 20 °C for 18 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was evaporated with <t> toluene (3 x 25 mL). The residue was dissolved in water (3mL) and the solution was added concentrated NH ₄ OH (1mL). After 2 hours at 20 ° C, the solvent was removed in vacuo. By flash chromatography (using a gradient of 5 to 50% of methanol in DCM) to afford a white solid was obtained as the purified compound 2 (14mg).

Example 3

Compound 4-1 (5.0 g, 8.5 mmol) and 2-amino-6-chloroindole (3.0 g, 17.7 mmol) were co-concentrated three times with anhydrous toluene. DBU (7.5 g, 49 mmol) was added to a stirred suspension of a mixture (50 mL). The mixture was stirred at 0 °C for 15 minutes, and TMSOTf (15 g, 67.6 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 ° C for 15 minutes and then heated to 70 ° C overnight. The mixture was cooled to room temperature and diluted with EA (100 mL). The solution was washed with a saturated solution of NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, then concentrated under low pressure. By silica gel column (PE / EA: 15/1 to 3/1) to give the residue obtained was 4-2 (2.5g, 46.3%) of a white foam.

Under N _2, was added to the MMTrCl of 4-2 (10g, 15.7mmol), AgNO 3 (8.0g, 47mmol) and collidine (10 mL) in dry DCM (20mL) was carve small parts (14.5 g of , 47mmol). The mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was washed with saturated brine and with aqueous NaHCO _3. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc/EtOAc)

To a solution of 3-hydroxy-propanenitrile (3.51 g, 49.4 mmol) in anhydrous THF (100 mL). A solution of 4-3 (8.5 g, 9.35 mmol) in dry THF (100 mL) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction was quenched with water and EtOAc (EtOAc) Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. By silica gel column (DCM / MeOH = 100/1 to 20/1) to give the residue obtained was 4-4 (4.5g, 83%) of a white solid.

Compound 4-4 (1.5 g, 2.6 mmol) was co-concentrated 3 times with anhydrous pyridine. In dry pyridine was added to 4-4 (30mL) solution of ice in the TsCl (1.086g, 5.7mmol), and stirred at 0 ℃ the reaction mixture for 1 hour. The reaction was quenched with water and EtOAc (EtOAc) Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. By silica gel column (DCM / MeOH = 100/1 to 15/1) to afford a white solid was obtained of 4-5 (1.4 g, 73%) .

To a solution of 4-5 (4.22 g, 5.7 mmol. The reaction was purified by Na ₂ S ₂ O ₃ was quenched with a saturated aqueous solution, followed by extraction with EA (100mL). Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. By silica gel column (DCM / MeOH = 100/1 to 15/1) to give the residue obtained was 4-6 (4g, 73%) of a white solid.

DBU (3.67 g, 24 mmol) was added to a solution of 4-6 (4.0 g, EtOAc. The mixture was diluted with EA (80 mL). The solution was washed with brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. By silica gel column (DCM / MeOH = 100/1 to 20/1) to give the residue obtained was 4-7 (2g, 61%) of a white solid.

Add AgF (618mg, 4.9mmol) and I ₂ (500mg, 1.97mmol) in dry DCM (20mL) in a solution of a solution of 4-7 (500mg, 0.89mmol) in dry DCM (20mL) in the cold. The mixture was stirred at room temperature for 3 hours. The reaction was, and the mixture was extracted with DCM (50mL) with saturated Na ₂ S ₂ O ₃ and quenched with aqueous NaHCO _3. The organic layer was separated, dried over anhydrous Na ₂ SO _4, and concentrated to give 4-8 (250mg, crude) as a yellow solid of crude product.

To a solution of the crude product 4-8 (900 mg, EtOAc. The mixture was stirred overnight at room temperature. The mixture was washed with saturated aqueous NaHCO ₃ and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc EtOAc :EtOAc

To a solution of the crude product 4-9 ( EtOAc, EtOAc (EtOAc) The mixture was stirred at 60 ° C for 2 days. The mixture was diluted with EA and the solution was washed with brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. By prep TLC (PE / EA = 1: 1) to obtain the residue was purified as a white solid of crude product 4-10 (550mg, 73%).

The crude product 4-10 (550mg, 0.6mmol) was dissolved in NH ₃ / MeOH in (7N, 50mL). The mixture was stirred overnight at room temperature. The mixture was concentrated, and by silica gel column (DCM / MeOH 100/1 to 20/1) to afford a white solid was obtained of 4-11 (62mg, 17%). ESI-MS: m/z 598.0 [M+H] ⁺ .

A solution of 4-11 (12 mg) in 80% formic acid (0.5 mL) was stood at room temperature for 3.5 hr then concentrated. The residue was co-evaporated 4 times with MeOH / toluene in EtOAc then EtOAc EtOAc. The EtOAc solution was removed with a pipette and the wet milling step was repeated several times. The remaining solid was dissolved in MeOH. The solution was concentrated and dried to give compound 4 (4.7 mg). ESI-MS: m/z 326.6 [M+H] ⁺ .

Example 4

To a solution of 5-1 (1.2 g; 4.3 mmol) in dioxane (30 mL), EtOAc (EtOAc, EtOAc (EtOAc) The mixture was stirred overnight at room temperature. The mixture was then neutralized with a methanolic ammonia solution and the solvent was evaporated. In the silica gel column (CH ₂ Cl ₂ -MeOH having a solvent system (4-10% gradient)) to afford the 5-2 (1.18g, 87%).

To an ice-cold solution of 5-2 (0.91 g; 2.9 mmol) EtOAc. The mixture was stirred at 0 ° C for 20 minutes. A solution of the chlorophosphate reagent (2.2 g; 2.5 equivalents) in THF (2 mL) was added dropwise. The mixture was stirred overnight at room temperature. With saturated aqueous NH ₄ Cl The reaction was quenched and stirred at room temperature for 10 minutes. Then with water and the mixture was diluted with CH ₂ Cl _2, and the two layers separated. The organic layer was washed with water, half saturated NaHCO ₃ solution and brine, and dried over Na ₂ SO _4. In the silica gel column (CH ₂ Cl ₂ -iPrOH having a solvent system (gradient 4-10%)) was purified to obtain the residue was evaporated Rp / Sp mixture of 5-3 (1.59g; 93%).

A mixture of 5-3 (1.45 g; 2.45 mmol) and 80% aqueous HCOOH (7 mL) was stirred at room temperature for 1.5 hr. The solvent was evaporated and co-evaporated with toluene. The obtained residue was dissolved in MeOH (3 drops) was treated with Et ₃ N and the solvent evaporated. In the silica gel column (CH ₂ Cl ₂ -MeOH having a solvent system (4-10% gradient)) to afford the Rp / Sp mixture of compound 5 (950mg; 70%). ³¹ P-NMR (DMSO-d ₆ ): δ 3.52, 3.37. MS: m/z = 544 [M-1].

Example 5

Compound 6

Compound 32-1 (5 g, 8.79 mmol) was co-evaporated with anhydrous pyridine. 32-1 was added to an ice cold solution of dry pyridine in the (15mL) in TsCl (3.43g, 17.58mmol), and stirred at 0 ℃ 1 hour. The reaction was checked by LCMS and TLC. The reaction was quenched with H ₂ O, and extracted with EA. The organic phase was dried over anhydrous Na ₂ SO _4, and the low pressure evaporator. Compound 6-1 (6.35 g, 100%) was used directly in the next step.

To a solution of 6-1 (31.77 g, 43.94 mmol) in EtOAc (30 mL). The reaction was checked by LCMS. The reaction was quenched with aq. sat. Na ₂ S ₂ O ₃ and extracted with EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. By silica gel column chromatography (with the DCM MeOH, 1-6%) to afford a white solid was obtained of 6-2 (11.5g, 38%).

To a solution of 6-2 (11.5 g, 16.94 mmol) EtOAc (EtOAc) The reaction was stirred overnight and checked by LCMS. The reaction was quenched with saturated NaHCO ₃ solution and extracted with EA. The organic phase was dried over anhydrous Na ₂ SO _4, and the low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut

Add AgF (618mg, 4.9mmol) and I ₂ (500mg, 1.97mmol) in dry DCM (20mL) in a solution of 6-3 (500mg, 0.90mmol) in dry DCM (20mL) in the ice cold solution. The reaction was stirred for 3 h and was checked by LCMS. With ₂ S ₂ O ₃ saturated solution and with saturated solution of Na NaHCO ₃ The reaction was quenched, and the mixture was extracted with DCM. By organic layer was dried over anhydrous Na ₂ SO _4, and evaporated to give the crude product low pressure 6-4 (420mg, 66%).

Add DCM (0.28 g, 2.33 mmol), TEA (145 mg, 1.44 mmol) and BzCl (230 mg, 1.62 mmol) of DCM to a solution of crude product 6-4 (250 mg, 0.36 mmol) (2 mL) solution. The reaction was stirred overnight and checked by LCMS. ₃ and the mixture was washed with a saturated solution of NaHCO brine. The organic layer is evaporated at a low pressure. The residue was purified by preparative EtOAc (EtOAc)

In dry solution of crude 6-5 (650mg, 0.72mmol) HMPA ( 20mL) in a solution of NaOBz (1.03g, 7.2mmol) and 15-crown--5 (1.59g, 7.2mmol). The reaction was stirred at 60 ° C for 2 days. The mixture was diluted with H ₂ O, and extracted with EA. The organic layer is evaporated at a low pressure. The residue was purified by preparative TLC to afford 6-6 (l. ESI-MS: m/z: 900.4 [M+H] ⁺ .

Stirring 6-6 (25mg) and BuNH ₂ (0.8mL) at room temperature overnight the mixture. The mixture was evaporated and the silica gel (10g column with _{CH 2 Cl 2 / MeOH (4-15} % gradient)) to afford the 6-7 (15mg, 91%).

A mixture of 6-7 (15 mg, 0.02 mmol) in ACN (0.25 mL) and 4N HCI / dioxane (19 μL) was stirred at room temperature for 45 min. The mixture was diluted with MeOH and evaporated. The crude residue was treated with MeCN, and filtered to obtain a solid compound 6 (7mg). MS: m/z = 314 [M-1].

Example 6

Compound 7

A mixture of 7-1 (170 mg, 0.19 mmol) and methanolic ammonia (7N; 3 mL) was stirred at room temperature for 8 hrs, and concentrated in EtOAc (10 g column with CH ₂ Cl ₂ /MeOH (4-11% gradient) )) was purified to obtain 7-2 (100 mg, 90%).

Compound 7-2 was rendered free by co-evaporation with pyridine followed by toluene. Chlorophosphate (50 mg, 3.5 equivalents) was added to a solution of 7-2 (24 mg, 0.04 mmol) and N-methylimidazole (17 mL, 5 eq.) in acetonitrile (1 mL). The mixture was stirred at room temperature for 1 day and evaporated. On Silica (10g column with _{CH 2 Cl 2 / MeOH (4-12} % gradient)) to afford 7-3 (10mg, 28%).

A solution of 7-3 (9 mg, 0.01 mmol) in 80% formic acid was stirred at room temperature for 3 hr. The mixture was evaporated and the Silica (10g column with _{CH 2 Cl 2 / MeOH (5-15} % gradient)) to obtain the purified compound 7 (3mg, 50%). MS: m/z = 624 [M-1].

Example 7

Compound 8

To an ice-cold solution of 8-1 (80 mg; 015 mmol) EtOAc (EtOAc) The mixture was stirred at 0 ° C for 20 minutes. A solution of the chlorophosphate reagent (0.16 g; 0.45 mmol) in THF (0.5 mL) was added dropwise. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH ₄ Cl and stirred at room temperature for 10 minutes. The mixture was diluted with water and CH ₂ Cl ₂ and the layers were separated. The organic layer was washed with water, half saturated NaHCO ₃ solution and brine, and dried over Na ₂ SO _4. In the silica gel column (CH ₂ Cl ₂ -MeOH having a solvent system (gradient 2-10%)) was purified to obtain the residue was evaporated Rp / Sp mixture of 8-2 (102mg; 80%).

It was stirred under H ₂ atmosphere of 8-2 (100mg; 0.12mmol) in a mixture of EtOH (3mL) and 10% Pd / C (10mg) in the 1.5 hours. Pad of diatomaceous earth mixture was filtered, evaporated and the silica gel column (CH ₂ Cl ₂ -MeOH having a solvent system (4-10% gradient)) to afford the Rp / Sp mixture (52mg, 74%) of Compound 8. MS: m/z = 584 [M-1].

Example 8

Compound 9

A mixture of 9-1 (1.2 g, 4.3 mmol), PTSA (0.82 g, 1 eq.) and trimethyl orthoformate (14 mL, 30 eq.) in dioxane (30 mL) was stirred overnight. With 7N NH ₃ / MeOH and the reaction was removed by filtration as a white solid. The residue was dissolved in THF (10 mL)EtOAcEtOAcEtOAc The mixture was kept at room temperature for 45 minutes and then evaporated. On silica gel (25g column with _{CH 2 Cl 2 / MeOH (4-10} % gradient)) obtained residue was purified on 9-2 (1.18g, 87%).

From 9-2 (93 mg, 0.29 mmol) and bis(isopropoxycarbonyloxymethyl)phosphoric acid triethylammonium (0.44 mmol) with DIPEA (0.2 mL), BopCl (147 mg) and 3-nitro-1 Compound 2-3 (137 mg, 75%) was obtained from THF (3 mL). Purification was carried out using a CH ₂ Cl ₂ /i-PrOH solvent system (3-10% gradient).

A solution of 9-3 (137 mg) in 80% aqueous HCOOH was stirred at room temperature for 2 hr then concentrated. The residue with toluene, containing a small amount and then Et ₃ N (2 drops) of co-evaporated with MeOH. In Silica (25g column with _{CH 2 Cl 2 / MeOH (4-10} % gradient)) to afford the compound 9 (100mg, 77%). MS: m/z = 1175 [2M-1].

Example 9

Compound 10

Compound 10-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated three times with dry toluene. DBU (39.5 g, 258.0 mmol) was added to a solution of 10-1 in MeCN (200 mL). The mixture was stirred at 0 ° C for 30 minutes, then TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 ° C for 30 minutes. The mixture was heated to 70 ° C and stirred overnight. The solution was cooled to room temperature and diluted with EA (100 mL). The solution was washed with a saturated solution of NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, and concentrated under low pressure. In the silica gel column (inclusive of PE EA, 10-40%) was obtained residue was purified on a yellow foam of 10-2 (48.0g, yield: 88.7%). ESI-MS: m/z 628 [M+H] ⁺ .

Under N _2, to 10-2 (48.0g, 76.4mol), AgNO 3 (50.0g, 294.1mmol) and collidine (40 mL) in dry DCM (200mL) was added in small portions a solution of MMTrCl (46.0 g, 149.2 mmol). The mixture was stirred at room temperature under N ₂ for 3 hours. The reaction was monitored by TLC. The mixture was filtered, and washed with saturated NaHCO ₃ solution and brine filter. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. By silica gel column (inclusive of PE EA, 5-50%) to afford the crude product obtained was 10-3 (68g, 98%). ESI-MS: m/z 900.1 [M+H] ⁺ .

Sodium (8.7 g, 378.0 mmol) was dissolved in anhydrous EtOH (100 mL) at EtOAc. Compound 10-3 (68.0 g, 75.6 mmol) was taken from a freshly prepared NaOEt solution and stirred at room temperature overnight. The reaction was monitored by TLC and the mixture was concentrated at low pressure. The mixture was diluted with H ₂ O (100mL), and extracted with EA (3 × 100mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. By silica gel column chromatography (DCM MeOH containing of 1% to 5%) was obtained as the residue was purified 10-4 (34.0g, 75.2%) of a yellow solid. ESI-MS: m/z 598 [M+H] ⁺ .

Compound 10-4 (32.0 g, 53.5 mmol) was co-evaporated 3 times with anhydrous pyridine. TsCl (11.2 g, 58.9 mmol) of pyridine (50 mL) was added dropwise to ice-cooled solution of 10-4 in anhydrous pyridine (100 mL). The mixture was stirred at 0 ° C for 18 hours. The reaction was checked by LCMS (about 70% of the desired product). Quenched with H ₂ O reaction, the solution was concentrated and the low pressure. The residue was dissolved in EA (100mL), and washed with saturated NaHCO ₃ solution. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc EtOAc. ESI-MS: m/z 752 [M+H] ⁺ .

NaI (45.9 g, 306.0 mmol) and TBAI (2.0 g) were added to a solution of 10-5 (23.0 g, 30.6 mmol) in EtOAc (150 mL). The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (100mL), washed with brine, and dried over anhydrous Na ₂ SO _4. Evaporate the organic solution at low pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc DBU (14.0 g, 91.8 mmol) was added to aq. The mixture was stirred overnight and checked by LCMS. ₃ The reaction was quenched with saturated NaHCO, solution and extracted with EA (100mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc EtOAc. ESI-MS: m/z 580 [M+H] ⁺ .

NIS (3.9 g, 17.2 mmol) and TEA® 3HF (3.3 g, 20.7 mmol) were added to an ice-cold solution of 10-6 (8.0 g, 13.8 mmol) in anhydrous MeCN (100 mL). The mixture was stirred at room temperature for 18 hours and checked by LCMS. After completion of the reaction, the reaction was neutralized with saturated Na ₂ SO ₃ and quenched with saturated NaHCO ₃ solution used. The solution was extracted with EA. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc ESI-MS: m/z 726 [M+H] ⁺ .

To a solution of the crude product 10-7 (7.2 g, EtOAc. The mixture was stirred overnight and checked by LCMS. The mixture was washed with a saturated solution of NaHCO _3. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc ESI-MS: m/z 934 [M+H] ⁺ .

To a solution of 10-8 (7.5 g, 8.0 mmol) EtOAc. The mixture was stirred at 90 ° C for 36 hours. The mixture was diluted with H ₂ O (100mL), and extracted with EA (3 × 150mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: ESI-MS: m/z 928 [M+H] ⁺ .

Compound 10-9 (4.0g, 4.3mmol) and dry toluene coevaporated three times, and treated with _{NH 3 / MeOH (50mL, 4N} ) at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction was monitored by LCMS and the mixture was concentrated at low pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc ESI-MS: m/z 616 [M+H] ⁺ .

Compound 10-10 (300.0 mg, 0.49 mmol) was co-evaporated three times with dry toluene and dissolved in MeCN (2 mL). The mixture was treated with NCN (120.5 mg, 1.47 mmol) and chlorophosphoric acid reagent (338.1 mg, 0.98 mmol) in MeCN (1 mL). The mixture was stirred at room temperature for 18 hours. The reaction was monitored by LCMS. The mixture was diluted with 10% NaHCO ₃ solution and extracted with EA. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc ESI-MS: m/z 925 [M+H] ⁺ .

Compound 10-11 (240.0 mg, 0.26 mmol) was taken eluted eluted elute The reaction was monitored by LCMS. Concentrate the mixture at low pressure. By silica gel column chromatography (with the DCM MeOH, 1-3%) to afford compound was obtained as a solid of 10 (87.6mg, 51.7%). ESI-MS: m/z 653 [M+H] ⁺ .

Example 10

To a suspension of 12-1 (20.0 g, 81.3 mmol), imidazole (15.9 g, 234.0 mmol), PPh ₃ (53.5 g, 203.3 mmol) and pyridine (90 mL) in anhydrous THF (100 mL) was added dropwise I ₂ (41.3g, 162.6mmol) in (150 mL) in a solution of THF. The mixture was slowly warmed to room temperature and stirred for 14 hours. The reaction was quenched with aqueous (150 mL) saturated Na ₂ S ₂ O ₃ and extracted with THF / EA (1/1) (100mL × 3). The organic layer was dried over Na ₂ SO _4, and concentrated under low pressure. The residue was recrystallized from EtOH to obtain a white solid of pure 12-2 (23g, 79%).

At room temperature to 12-2 (23g, 65mmol) in anhydrous (200mL) was stirred in a solution of MeOH was added containing NaOCH ₃ (10.5g, 195mmol) of MeOH (50mL). The mixture was stirred at 60 ° C for 3 hours and quenched with dry ice. The solid precipitated and was removed by filtration. Concentrate the filtrate at low pressure. In column silica gel (DCM MeOH containing of 1% to 10%) was obtained as a residue was purified on 12-3 (13.1g, 92.5%) of a white foamy solid.

At 0 ℃, the 12-3 (12.0g, 53mmol) in dry CH ₃ CN was added to stir the TEA˙3HF (8.5g, 53mmol) and NIS (10.2g, 63.6mmol). The mixture was stirred for 30 minutes and slowly warmed to room temperature. The mixture was stirred for another 30 minutes. The solid was removed by filtration, and washed with DCM to obtain a yellow solid of 12-4 (14g, 73%). ESI-MS: m/z 373.0 [M+H] ⁺ .

At room temperature, to 12-4 (12.0g, 32mmol) and DMAP (1.2g, 9.6mmol) in pyridine was (100 mL) was stirred in a solution of _{Bz 2 O (21.7g, 96mmol)} . The mixture was stirred at 50 ° C for 16 hours. The resulting solution was quenched with water and concentrated to dryness under reduced pressure. The crude product was purified on a EtOAc EtOAc EtOAc (EtOAc) ESI-TOF-MS: m/z 581.0 [M+H] ⁺ .

Tetrabutylammonium hydroxide (288 mL in the form of a 54-56% aqueous solution, 576 mmol) was adjusted to a pH of about 4 by the addition of TFA (48 mL). The resulting solution was treated with a solution of 12-5 (14 g, 24 mmol) in DCM (200 mL). The m-chloroperbenzoic acid (30 g, 60-70%, 120 mmol) was added portionwise with vigorous stirring, and the mixture was stirred overnight. The organic layer was separated and washed with brine. The resulting solution was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography to afford 12-6 (7.5 g, 68%).

Compound 12-6 (5.0g, 10.6mmol) was treated with 7N NH ₃ ˙MeOH (100mL), and the mixture was stirred for 5 hours. The mixture was then concentrated to dryness under reduced pressure. The residue was washed with EtOAc (EtOAc m .) ESI-MS: m/z 263.0 [M+H] ⁺ .

TIDPSCl (2.5 g, 8.0 mmol) was added dropwise to a solution of 12-7 (2.1 g, 8.0 mmol) in pyridine at 0 ° C and stirred at room temperature for 12 hr. The solution was quenched with water and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography ( EtOAc EtOAc ( EtOAc : EtOAc)

It was stirred at 80 ℃ 12-8 (1.5g, 3.0mmol) and IBX (1.69g, 6.0mmol) in dry CH of the ₃ CN (10mL) solution for 3 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness at low pressure. The residue was purified by column chromatography ( EtOAc EtOAc EtOAc ) ESI-MS: m/z 503.0 [M+H] ⁺ .

Compound 12-9 (500 mg, 1 mmol) was dissolved in dry THF (8 mL). Magnesium bromide bromide (8 mL, 0.5 M solution in cyclohexane) was added at room temperature. After 30 minutes, additional magnesium bromide (8 mL) was added. The mixture was held for 30 minutes and then quenched with a saturated solution of ammonium chloride. The product was extracted with EA. The organic extract was washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel in EA to remove darkness. The yellow compound was dissolved in THF (3 mL) and EtOAc (EtOAc) The solvent was evaporated and the residue was chromatographed on a Biotage filter (25 g). The EA saturated with water was used for isocratic dissolution. Each fraction was analyzed by TLC in DCM:MeOH (9:1 v: v). The fractions containing the isomers containing only high Rf were concentrated to give the pure compound 12 (110 mg). MS: 285.1 [M-1].

Example 11

Compound 12 (57mg, 0.2mmol) was dissolved in CH containing N- methylimidazole (40 L) of ₃ CN (2mL) in. Chlorophosphate reagent (207 mg, 0.6 mmol) was added and the mixture was kept at 40 ° C overnight. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The product was isolated by silica gel chromatography (0% to 15% gradient of methanol in DCM). Compound 13 (46 mg, 39%) was obtained. MS: m/z 593.9 [M-1].

Example 12

IBX (7.66 g, 27.34 mmol) was added to a stirred solution of 14-1 (5.0 g, 19.53 mmol). The mixture was heated at 80 ° C for 12 hours and then slowly cooled to room temperature. After filtration, the filtrate was concentrated to give crude material 14-2 (······

At -78 deg.] C in N of anhydrous THF was added dropwise a solution of methyl magnesium bromide (19.53mL, 58.59mmol) ₂ under to 14-2 (4.96g, 19.53mmol). The mixture was slowly warmed to room temperature and stirred for 12 hours. With saturated NH ₄ Cl solution, the mixture was quenched and extracted with EA. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by silica gel column was obtained as a white solid of 14-3 (4.37g, 83%).

Add DMAP (3.95 g, 32.38 mmol), TEA (4.91 g, 48.56 mmol) and BzCl (6.80 g, 48.56) to a solution of 14-3 (4.37 g, 16.19 mmol) in dry EtOAc. Mm). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO ₃ solution (30mL), and extracted with EA (3 × 50mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by silica gel column was obtained as 14-4 (5.3g, 87%) of a white solid.

At 0 ℃, (3.0g, 8.02mmol) and Ac ₂ O (4.91g, 48.13mmol) in acetic acid (10 mL) was added in the concentration of H ₂ SO ₄ (98% to 14-4, 2.41g, 24.06 Mm). The mixture was stirred at room temperature for 12 hours. The solution was poured into ice water (30 mL) and extracted with EtOAc EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc elut elut elut elut

At 0 ℃, under N _2, in the 6-Cl- to guanine (560mg, 3.31mmol) and 14-5 (1.11g, 2.76mmol) in dry MeCN (5mL) under nitrogen was added DBU (1.27 g, 8.28 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0 ° C and TMSOTf (2.45 g, 11.04 mmol) was slowly added over 15 min. The mixture was then warmed to room temperature over 30 minutes. The mixture was heated at 60 ° C for 4 hours. The mixture was poured into ice water (30 mL) and extracted with EtOAc EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

, In the MMTrCl (1.46g, 4.75mmol) and AgNO ₃ (697mg, 4.1mmol) in DCM (10mL) was added collidine (794mg, 6.56mmol) to 14-6 (839mg, 1.64mmol). The mixture was stirred at room temperature for 12 hours. With a saturated solution of NaHCO ₃ (20mL) The reaction was quenched. After filtration, the filtrate was extracted with DCM (3×20 mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc EtOAc .

3-Hydroxyacrylonitrile (4.13 g, 5.82 mmol) was dissolved in dry THF (10 mL). The solution was treated with NaH (464 mg, 11.6 mmol) at 0 ° C and slowly warmed to room temperature and stirred for 30 min. A solution of 14-7 (912 mg, 1.16 mmol) in dry THF (5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with EtOAc (EtOAc)EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc elut elut elut elut

In dry pyridine (10 mL) in added dropwise a solution of TsCl (4.54g, 23.89mmol) in anhydrous pyridine (10 mL) in a solution of 14-8 (6.20g, 10.86mmol) at 0 ℃. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water (30 mL)EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

To a solution of 14-9 (6.0 g, 8. <RTI ID=0.0></RTI></RTI><RTIgt; The mixture was evaporated under reduced pressure. The residue was dissolved in EA (50mL), and washed with saturated NaHCO ₃ solution (30mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by silica gel column was obtained as a white solid of 14-10 (5.43g, 96.4%).

To 14-10 (5.0g, 7.34mmol) in dry THF was added DBU (4.49g, 29.37mmol) (20mL ) in the solution, and stirred overnight at 60 ℃. The mixture was slowly cooled to room temperature. The mixture was quenched with water (30 mL)EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc EtOAc .

To a solution of 14-11 (3.5 g, 6.33 mmol) and EtOAc (4. <RTI ID=0.0></RTI></RTI><RTIgt; Solution in 5 mL). The mixture was stirred for 3 hours. The reaction mixture was washed and extracted with EA ₍₃ × 50mL) NaHCO 3 saturated solution (40mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc elutcd

Sodium benzoate (2.82 g, 19.60 mmol) and 15-crown-5 (4.31 g, 19.60 mmol) were added to a solution of 14-12 (1.37 g, 1.96 mmol) in anhydrous DMF (15 mL). Stir for 3 days. The mixture was quenched with water (30 mL)EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by HPLC to give 14-13 (250 mg, 20%). ESI-MS: m/z: 694 [M+H] ⁺

A mixture of 14-13 (250 mg, 0.36 mmol) in liquid ammonia was maintained in a high pressure glass vessel overnight at room temperature. Then ammonia was evaporated, and the silica gel (10g column with _{CH 2 Cl 2 / MeOH (4-10} % gradient)) obtained residue was purified on 14-14 (180mg, 85%).

THF (2 mL) containing i-PrMgCl (0.11 mL) and chlorophosphoric acid reagent (94 mg) was used to afford compound 14 (85 mg, 56%) from 14-14 (99 mg). MS: m/z = 627 [M + 1].

Example 13

Compound 15

To 15-1 (260mg, 1mmol), PPh 3 (780mg, 3mmol) and pyridine (0.5mL) at room temperature in dry THF (8mL) was added in the I ₂ (504mg, 2mmol), and at room temperature The mixture was stirred for 12 hours. The mixture was diluted with EtOAc and washed with 1M EtOAc. The organic layer was dried over Na ₂ SO _4, filtered and concentrated under low pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc

DBU (760 mg, 5 mmol) was added to a solution of 15-2 (190 mg, 0.52 mmol) in THF (4 mL), and the mixture was heated at 50 ° C overnight. The mixture was diluted with EtOAc and washed with water. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc)

NIS (337 mg, 1.5 mmol) and TEA ̇3HF (213 mg, 1.25 mmol) were added to a solution of 15-3 (200 mg, 0.82 mmol The mixture was 7 hours. The reaction was quenched with _saturated aqueous Na ₂ SO ₃ and saturated solution of NaHCO. The mixture was extracted with EA. The organic layer was separated, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

To a solution of 15-4 (194 mg, 0.5 mmol) in EtOAc (5 mL) The mixture was stirred at room temperature for 5 hours and the reaction was quenched with water. Mixture was concentrated under low pressure and by silica gel column (inclusive of PE 20% EA) to afford the residue obtained as a white solid of 15-5 (397mg, 81%).

To 15-5 (1.05g, 2.13mmol) in DCM was added TFA (0.5mL) (12mL) in a solution of a mixture of Bu ₄ NOH (1mL), the subsequently added m -CPBA (1.3g at room temperature, 6mmol ). The mixture was stirred at room temperature for 5 hours. The mixture was washed with a saturated Na ₂ SO ₃ solution and aqueous NaHCO ₃ solution. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc)

Compound 15-6 (250mg, 0.65mmol) was dissolved in (5mL) in NH ₃ / MeOH. The mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. By silica gel column (5% MeOH in the DCM) was obtained residue was purified by 15 (120mg, 66%) as a white powder of the compound. ESI-MS: m/z 279.0 [M+H] ⁺ .

Example 14

Sodium (6.0 g, 261.2 mmol) was dissolved in anhydrous EtOH (400 mL). Compound 14-7 (32.0 g, 43.5 mmol) was treated with a freshly prepared NaOEt solution at 0 ° C and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC and LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was quenched with H ₂ O (40mL), and extracted with EA (3 × 50mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc

Compound 16-1 (20.0 g, 33.3 mmol) was co-evaporated 3 times with anhydrous pyridine. TsCl (9.5 g, 49.9 mmol) was added to an ice-cold solution (100 mL) of 16-1 in anhydrous pyridine at 0 °C. After the addition, the reaction was stirred at 20 ° C for 12 h and was monitored by LCMS. The reaction was quenched with H ₂ O, and the low-pressure concentrated. The residue was dissolved in EA (50 mL). The solution was washed with a saturated solution of NaHCO ₃ and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

To a solution of 16-2 (20.0 g, 26.5 mmol) in EtOAc (EtOAc)EtOAc. The reaction was checked by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (50 mL). The solution was washed with brine. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc DBU (16.2 g, 106 mmol) was added to a solution of EtOAc. The mixture was stirred overnight and checked by LCMS. The reaction was quenched with saturated NaHCO ₃ solution, and extracted with EA (3 × 50mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and the low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc EtOAc.

NIS (5.4 g, 23.7 mmol) and NEt ₃ ̇ 3HF (3.0 g, 18.9 mmol) were added to an ice-cooled solution of 16-3 (11.0 g, 18.9 mmol) in anhydrous MeCN (100 mL). The mixture was stirred at room temperature for 4 hours and checked by LCMS. After completion of the reaction, the reaction solution was ₂ SO ₃ and saturated NaHCO ₃ solution was quenched with saturated Na. The solution was extracted with EA (3 x 100 mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and the low pressure evaporator. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc)

To a solution of 16-4 (10.0 g, 13.7 mmol) EtOAc. The reaction was stirred at 90 ° C for 48 hours and diluted with EA. The solution was washed with water and brine and dried over MgSO ₄ The organic layer was evaporated at low pressure and the residue was purified by EtOAc EtOAc EtOAc EtOAc

Compound 16-5 (6.0g, 8.3mmol) in dry toluene and co-evaporated three times with and containing the NH MeOH ₃ (4N, 50 mL) at room temperature. The reaction was stirred at room temperature for 18 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by hydrazine column chromatography (EtOAc EtOAc, 20% to 50%) to afford 16-6 (4.5 g, 87.8%). ESI-MS: m/z 617.9 [M+H] ⁺ .

To the ice-cold mixture of 16-6 (25 mg, 0.07 mmol Additional amounts of NMI (46 μL) and chlorophosphate reagent (73 mg) were added and stirring was continued for 1 day. The reaction was quenched with saturated aqueous NH ₄ Cl, diluted with EtOAc and water. The organic layer was separated and washed with aqueous NaHCO _3, water and brine, then dried (Na ₂ SO _4). On silica gel (10g column with _{CH 2 Cl 2 / i-PrOH} (4-10% gradient)) obtained residue was purified by 16 (18mg, 40%) compound. MS: m/z = 655 [M + 1].

Example 15

To a solution of compound 15 (139 mg, 0.5 mmol) in EtOAc (5 mL) The mixture was stirred at room temperature for 5 hr, diluted with EtOAc andEtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc)

TPSCl (604 mg, 2 mmol) was added to a solution of 18-1 (490 mg, 1 mmol), DMF (244 mg, 2 mmol) and TEA (205 mg, 2.1 mmol) in MeCN (10 mL). The mixture was stirred at room temperature for 2 hours, followed by addition of an aqueous NH ₄ OH solution at room temperature. The mixture was stirred for 0.5 hours, diluted with EtOAc and washed with saturated aqueous NaHCO ₃ and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc)

Compound 18-2 (250mg, 0.51mmol) was dissolved in NH ₃ / MeOH (15mL) in. The mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. By silica gel column (with 5% DCM DCM's) Purification of the residue obtained as a white powder of the compound 18 (95mg, 66%). ESI-MS: m/z 278.1 [M+H] ⁺ .

Example 16

At -78 ℃, under N _2, a solution of compound 20-1 (30g, 0.08mol) in dry THF (300mL) was added dropwise in the added lithium triethylborohydride - tert-butoxy aluminum hydride (120mL, 0.12 Mol). The mixture was stirred at -20 ° C for 1 hour. The reaction was quenched with saturated aqueous NH ₄ Cl, followed by filtration. The filtrate was extracted with EA (3×300 mL). Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc)

At -20 ℃, under N _2, was added compound 20-2 (27g, 0.072mol) was stirred in to the PPh ₃ (37.7g, 0.144mol) in DCM (100mL) over a solution. After the mixture was stirred at room temperature for 15 minutes, CBr ₄ (42 g, 0.129 mol) was added while maintaining the reaction temperature at -25 to -20 ° C under N ₂ . The mixture was then stirred at -17 ° C for 20 minutes. The tannin extract is added to the solution, followed by separation and purification by flash column to obtain a crude oily product. The crude product was purified by a silica gel column (2% to 20% of EA) to afford 20-3 ( y -isomer, 17 g, 55%) as colorless oil.

The mixture of 6-Cl-guanine (11.6 g, 68.8 mmol) and t-BuOK (8.2 g, 73 mmol) in t-BuOH (200 mL) and MeCN (150 mL) was stirred at 35 ° C for 30 min. 20-3 (10 g, 22.9 mmol) of MeCN (100 mL) was added. The mixture was heated at 50 ° C overnight. The reaction was treated with NH ₄ Cl (5g) in water (40 mL) of the solution was quenched and the mixture was filtered. The filtrate was evaporated at a low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

Add AgNO ₃ (8.1 g, 47.6 mmol), trimethylpyridine (5.77 g, 47.6 mmol) and MMTrCl (11 g, 35.7 mmol) to a solution of 20-4 (12.5 g, 23.8 mol) in DCM (50 mL) . The mixture was stirred overnight at room temperature. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAc m. To a solution of HOCH ₂ CH ₂ CN (4.7 g, 66 mmol) in THF (200 mL). The mixture was stirred at room temperature for 30 minutes. A solution of the intermediate (10.5 g, 13 mmol) in EtOAc. The reaction was quenched with EtOAc (EtOAc)EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc:

The solution was added to the PPh ₃ (7.0g, 26.6mmol) in anhydrous pyridine _{(100mL) I 2 (6.3g,} 24.9mmol), and stirred at room temperature for 30 minutes. The mixture was treated with a solution of 20-5 (9.5 g, 16.6 mmol) in pyridine (40 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated ₂ S ₂ O ₃ Na solution and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

DBU (5.4 g, 33 mmol) was added to a solution of 20-6 (7.5 g, 11 mmol) in dry THF (50 mL), and the mixture was warmed to reflux for 4 hr. The mixture was diluted with EA (3 x 100 mL) and washed with brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc)

TEA ̇3HF (0.65 g, 4.1 mmol) and NIS (1.53 g, 6.78 mmol) were added to an ice-cold solution of 20-7 (3.0 g, 5.4 mmol) in anhydrous MeCN (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (50mL), and washed with Na ₂ S ₂ O ₃ solution and saturated aqueous NaHCO _3. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated to dryness. The residue was purified by preparative HPLC (water containing 0.1% HCOOH and MeCN) to isolate the two isomers (about 1:1). The NOE showed a polarity of 20-8 (0.6 g, 16%) as a white solid.

To a solution of 20-8 (0.7 g, 1 mmol) in dry EtOAc (10 mL) The mixture was stirred at room temperature for 3 hours. The mixture was then diluted with EA, and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated at low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

To a solution of 20-9 (0.65 g, 0.8 mmol) EtOAc. The mixture was stirred at 100 ° C for 48 hours. The solvent was evaporated under reduced pressure and the residue was crystallised from EA (30mL) The organic layer was dried over Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

It was stirred at rt NH-containing compound 20-10 (400mg, 0.5mmol) of ₃ / MeOH (7N, 100mL) for 18 hours. The mixture was concentrated under reduced pressure and the residue was purified mjjjjjjjjjj ESI-MS: m/z 590.3 [M+H] ⁺ .

Compound 20-11 (59 mg, 0.1 mmol) was dissolved in methanol (10 mL) containing 50% TFA, and the mixture was kept at room temperature for 2 hr. The solvent was evaporated and co-evaporated with a methanol/toluene mixture to remove traces of acid. The residue was suspended in CH ₃ CN (1mL) and the centrifugation. The precipitate was washed with CH ₃ CN (1mL) was washed and dried. Compound 20 (21 mg, 65%) was obtained as a colorless solid. MS: m/z 316.2 [M-1].

Example 17

Of acetonitrile in the same manner as compound 7, self-contained 21-1 (50mg) of (2mL) phosphite with chlorine reagent (0.14 g of) and NMI (0.1mL) Preparation of Compound 21 (15mg, 16%). MS: m/z = 643 [M + 1].

Example 18

Of acetonitrile in the same manner as compound 7, self-contained 22-1 (50mg) of (2mL) phosphite with chlorine reagent (0.14 g of) and NMI (0.1mL) Preparation of Compound 22 (30mg, 32%). MS: m/z = 615 [M + 1].

Example 19

To a stirred solution of compound 15 (60 mg, 0.22 mmol A solution of phenylcyclohexyl-L-alanine)phenyl chlorophosphate (235 mg, 0.68 mmol, dissolved in THF (2 mL)). The resulting solution was stirred at 0 ° C for 1 hour, and the temperature was raised to 10 ° C over the next 1 hour. The reaction was held at 10 ° C for 3 hours. The mixture was cooled to 0 to 5 ° C, diluted with EA and water (5 mL). The solution was washed with H ₂ O and brine. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was dissolved in _{25% CH 3 CN / H 2} O in. The compound was purified by reverse phase HPLC (C18) using acetonitrile and water, followed by lyophilization to give a white foam. The product was redissolved in EtOAc, washed with 50% citric acid solution, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo and lyophilized to afford the two isomers of compound 23 (Rp/Sp) (6.3 mg). MS m/z 586.05 [MH].

Example 20

Add N-methylimidazole (236 μL, 2.87 mmol) to a stirred solution of compound 15 (100 mg, 0.36 mmol) in dry THF (3.0 mL). Solution (329 mg, 1.08 mmol, dissolved in 2 mL THF). The solution was stirred at 0 ° C for 1 hour, and the reaction temperature was raised to 10 ° C over the next 1 hour, and the solution was maintained at 10 ° C for the next 4 hours. The mixture was cooled to 0 to 5 ° C, diluted with EA and water (15 mL). The solution was washed with H ₂ O, 50% aqueous citric acid and brine. The organic layer was separated, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to obtain a residue which was dissolved in _{25% CH 3 CN / H 2} O in. Acetonitrile and water in the residue was purified on reverse phase HPLC (C18), followed by lyophilization to obtain a mixture of two isomers of Compound 24 (17.5mg). MS m/z 546.05 [MH].

Example 21

Compounds 25 and 26

Add AgNO ₃ (0.22 g, 1.29 mmol), trimethylpyridine (0.15 g, 1.29 mmol) and MMTrCl to a solution of 25-1 (0.47 g, 0.65 mol) in DCM (3 mL). 0.3 g, 0.974 mmol). The mixture was stirred overnight at room temperature. The mixture was filtered, and _saturated aqueous brine and filter with NaHCO. The organic layer was separated, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column silica gel was obtained as a white solid of 25-2 (0.55,85%).

To a solution of 25-2 (0.5 g, 0.5 mmol) EtOAc. The mixture was stirred at 95 ° C for 72 hours. The mixture was diluted with EA and washed with water and brine. The organic phase was dried over MgSO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

Stirred-containing compound 25-3 (0.3g, 0.3mmol) at room temperature and the NH ₃ / MeOH (30mL) 18 hours. The mixture was concentrated under reduced pressure and the residue was purified mjjjjjjjjjj ESI-LCMS: m/z 890.5 [M+H] ⁺ .

(161mg, 0.16mmol) in dry CH added N- methylimidazole of ₃ CN (2.0mL) was stirred at 0 to 5 ℃ (ice / water bath) was added to a solution of 25-4 (118μL, 2.87mmol), followed by was added a solution of 25-5 (186mg, 0.54mmol, was dissolved in 2mL CH ₃ CN in). The solution was stirred at 0 to 5 ° C for 4 hours. The mixture was diluted with EA and water (15 mL) was added. The solution was washed with H ₂ O, 50% aqueous citric acid and brine. The organic layer was separated, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to obtain a residue, which silica gel (with zero to 40% EA / hexanes) to obtain the purified (82.6 mg) and the slower eluting isomer of isomers from the fast dissolving 25-625-7 ( 106 mg).

Compound 25-6 (82.6mg, 0.07mmol) was dissolved in dry CH ₃ CN (0.5mL), and the in dioxane was added (35μL) 4N HCl at 0 to the 5 ℃. The mixture was stirred at room temperature for 1 hour, and anhydrous EtOH (100 μL) was added. The solvent was evaporated at room temperature and co-evaporated 3 times with toluene. The residue was dissolved in _{50% CH 3 CN / H 2} O in water and acetonitrile and purified on reverse phase HPLC (C18), followed by lyophilization to obtain Compound 25 (19.4mg). ¹ H NMR (CD ₃ OD-d ₄ , 400 MHz) δ 7.9 (s, 1H), 7.32-7.28 (t, J = 8.0 Hz, 2H), 7.2-7.12 (m, 3H), 6.43 (d, J = 17.6 Hz, 1H), 4.70-4.63 (m, 2H), 4.55-4.4 (m, 3H), 3.94-3.9 (m, 1H), 1.79-1.67 (m, 4H), 1.53-1.49 (m, 1H) , 1.45-1.22 (m, 15H); 31 P NMR (CD 3 OD-d 4) δ 4.06 (s); ESI-LCMS: m / z = 655.2 [m + H] +, 653.15 [MH] -.

Compound 25-7 (100mg, 0.083mmol) was dissolved in anhydrous CH ₃ CN (0.5mL), and was added in dioxane (50μL) 4N HCl at 0 to the 5 ℃. Following the procedure for obtaining compound 25 , Compound 26 (31.8 mg) was obtained. ¹ H NMR (CD ₃ OD-d ₄ , 400 MHz) δ 7.93 (s, 1H), 7.33 - 7.29 (m, 2H), 7.24 - 7.14 (m, 3H), 6.41 (d, J = 17.6 Hz, 1H) , 4.70-4.60 (m, 2H), 4.54-4.49 (m, 2H), 4.44 - 4.39 (m, 1H), 3.92-3.89 (m, 1H), 1.77-1.66 (m, 4H), 1.54-1.24 ( ^31, P NMR (CD ₃ OD-d ₄ ) δ 3.91 (s); ESI-LCMS: m/z = 655.2 [M+H] ⁺ , 653.1 [M - H] ^- .

Example 22

Add DBU (77.8 g) to a stirred suspension of 4-1 (50 g, 84.8 mmol) and 2-amino-6-chloroindole (28.6 g, 169.2 mmol) in anhydrous MeCN (500 mL). , 508 mmol). The mixture was stirred at 0 °C for 30 minutes, and TMSOTf (150.5 g, 678 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 20 minutes until a clear solution formed. The mixture was stirred overnight at 90-110 °C. The mixture was cooled to room temperature and diluted with EA. The solution was washed with a saturated solution of NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, then concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc/EtOAc)

To 27-1 (30g, 47.1mmol) in dry the DCM (300mL) was added collidine _{(30mL), AgNO 3 (24g} , 141.4mmol) and MMTrCl (43.6g, 141.4mmol). The mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate was washed with water and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc ( EtOAc /EtOAc)

A solution of EtONa in EtOH (2N, 150 mL) was added to a stirred solution of 27-2 (35 g, 38.5 mmol) in dry EtOH (150 mL). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was dissolved in EA (200 mL) and washed with water and brine. The organic layer was dried over Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc

Compound 27-3 (19 g, 31.3 mmol) was co-concentrated 3 times with anhydrous pyridine. 27-3 in dry ice to a solution of pyridine (120 mL) at 0 ℃ dropwise added TsCl (6.6g, 34.6mmol) in pyridine (40 mL) in the. The mixture was stirred at 0 ° C for 16 h. The mixture was quenched with water and the reaction mixture was concentrated. The residue was redissolved in EA (200 mL). And _saturated aqueous brine solution NaHCO. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered, and the filtrate was concentrated. The residue was purified with EtOAc EtOAc m .

To a solution of 27-4 (15 g, 19.7 mmol) in EtOAc (EtOAc) The mixture was refluxed overnight and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc

To 27-5 (8g, 11.2mmol) in anhydrous THF (60mL) was added in the DBU (5.12g, 33.5mmol), and the mixture was heated overnight at 60 deg.] C lower. The mixture was diluted with EA and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered, and the filtrate was concentrated. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc ) ¹ H-NMR (CD ₃ OH, 400 MHz) δ = 8.18 (s, 1H), 7.17-7.33 (m, 12H), 6.80 (d, J = 8.8 Hz, 2H), 5.98 (s, 1H), 5.40 ( d, J = 8.6 Hz, 1H), 3.87 (m, 5H), 3.75 (s, 3H), 2.69 (s, 1H), 1.05 (s, 3H).

To an ice-cold solution of 27-6 (4.44 g, 7.5 mmol) EtOAc (EtOAc) The mixture was stirred at room temperature for 2-3 hours. Reaction was quenched with saturated Na ₂ SO ₃ and NaHCO ₃ solution was quenched. The mixture was extracted with EA (3 x 100 mL). The organic layer was separated, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:

To a solution of 27-7 (5.36 g, 7.3 mmol) EtOAc (EtOAc m. The mixture was stirred overnight at room temperature. The mixture was washed with saturated aqueous NaHCO ₃ and brine. The organic layer was concentrated, EtOAc EtOAcjjjjjjjj

To a solution of 27-8 (5.0 g, 5.3 mmol) EtOAc (EtOAc) The mixture was stirred at 90-100 ° C for 48 hours. The mixture was diluted with EA and washed with water and brine. The organic layer was concentrated, and EtOAc EtOAcjjjjjjj

Was stirred in MeOH 27-9 containing compound of the NH ₃ (7N, 60mL) for 18 hours at room temperature. Concentrate the mixture at low pressure. The residue was purified by EtOAc EtOAc (EtOAc) ESI-MS: m/z 626.3 [M+H] ⁺ .

Add imidazole (50 mg, 0.72 mmol) and TBSCl (108 mg, 0.72 mmol) to a solution of 27-10 (350 mg, 0.56 mmol) EtOAc. 15 hours. The reaction was quenched with absolute EtOH (0.5 mL). The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EA (150mL), and the washed with water, washed with saturated NaHCO ₃ and brine. The combined organic layers were dried over Na ₂ SO _4, filtered and evaporated a low pressure. By silica gel column (10-30% EA in hexane of) the residue was purified to obtain a white solid of 27-11 (338mg, 81.8%).

Under N _2, was added in the MMTrCl (4mL) solution of compound 27-11 (328mg, 0.44mmol), AgNO 3 (226mg, 1.33mmol) and tri-methyl pyridine (0.59mL, 4.84mmol) in dry DCM ( 410 mg, 1.33 mmol). At room temperature under N _2, the mixture was stirred overnight, and monitored until complete by TLC. The mixture was filtered through a prepacked celite filter, and the filtrate was washed with water, 50% aqueous citric acid and brine. The organic layer was separated, dried over anhydrous Na ₂ SO _4, filtered and concentrated under low pressure. The residue was purified by a silica gel column (hexanes containing EA, 0% to 30%) to afford 27-12 (337 mg).

At 0 to 5 ℃, to 27-12 (337mg, 0.33mmol) in dry was added a solution of 1.0M TBAF (0.66ML, 0.66mmol) (4mL) in a solution of THF. The reaction was slowly warmed to room temperature and stirred for 1 hour. The mixture was quenched with silica gel and filtered. Evaporation of the solvent gave a crude material which was purified from EtOAc EtOAc ( EtOAc EtOAc

At 0-5 deg.] C (ice / water bath) to 27-13 (180mg, 0.16mmol) in dry CH of the ₃ CN (2.5mL) was added a stirred solution of N- methylimidazole (132μL, 1.6mmol), was then added (cyclohexyl acyl -L- alanine-yl) phenyl phosphate chloride solution (207mg, 0.6mmol, dissolved in 2mL CH ₃ CN). The solution was stirred at room temperature for 2.5 hours, and the mixture was diluted with EA, followed by water (15 mL). The solution was washed with H ₂ O, 50% aqueous citric acid and brine. The organic layer was separated, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was silica gel (with zero to 40% EA / hexanes) to obtain the purified 27-14 (75.8mg) and the slower eluting isomer 27-15 (108mg).

Compound 27-14 (76mg, 0.063.mmol) was dissolved in dry CH ₃ CN (0.5mL), and the in dioxane was added (47μL) 4N HCl at 0 to the 5 ℃ (ice / water bath). The mixture was stirred at room temperature for 40 minutes and anhydrous EtOH (200 μL) was added. The solvent was evaporated at room temperature and co-evaporated 3 times with toluene. The residue was dissolved in _{50% CH 3 CN / H 2} O and purified using acetonitrile and water on a reverse phase HPLC (C18), and lyophilized to obtain Compound 27 (26.6mg). ESI-LCMS: m/z = 663.3 [M+H] ⁺ .

Compound 27-15 (108mg, 0.089mmol) was dissolved in anhydrous CH ₃ CN (0.7mL), and was added in dioxane (67μL) 4N HCl at 0 to the 5 ℃ (ice / water bath). The mixture was stirred at room temperature for 60 minutes, and anhydrous EtOH (200 μL) was added. The solvent was evaporated at room temperature and co-evaporated 3 times with toluene. The residue was dissolved in _{50% CH 3 CN / H 2} O and purified using acetonitrile and water on a reverse phase HPLC (C18), and lyophilized to give compound 28 (40.3mg). ESI-LCMS: m/z = 663.2 [M+H] ⁺ .

Example 23

Compounds 30 and 31

Add 30-1 (50 g, 100 mmol) to a mixture of pre-alkylated 6-Cl-guanine (using HMDS and (NH ₄ ) ₂ SO ₄ ) (25.2 g, 150 mmol) in DCE (300 mL). ) and TMSOTf (33.3 g, 150 mmol). The mixture was stirred at 70 ° C for 16 hours and then concentrated under reduced pressure. The residue was dissolved in EA and washed with saturated aqueous NaHCO ₃ and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified on EtOAc (EtOAc/EtOAc)

To a solution of 30-2 (45 g, 73.4 mmol) in EtOAc (EtOAc) (EtOAc) The mixture was stirred at room temperature for 16 hours. The mixture was then concentrated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

TIPDSCl ₂ (19.2 g, 61 mmol) was added dropwise to a solution of 30-3 (19 g, 61.1 mmol) in pyridine (120 mL). The mixture was stirred at room temperature for 16 hours and then concentrated at low pressure. The residue was dissolved in EA and washed with saturated aqueous NaHCO _3. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified with EtOAc EtOAc EtOAc ( EtOAc :EtOAc

TMSCl (12.9 g, 119 mmol) was added dropwise to a solution of 30-4 (22 g, 39.8 mmol) in DMF / pyridine (5/1, 100 mL). The mixture was stirred at room temperature for 1 hour and then treated with isobutylphosphonium chloride (5.4 g, 50 mmol). The mixture was stirred at room temperature for 3 hours and then quenched by NH ₄ OH. Concentrate the mixture at low pressure. The residue was dissolved in EA (200 mL). , Then the organic layer was dried and concentrated to a low pressure washed with saturated aqueous NaHCO ₃ solution. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc :

At 0 ℃, was added to the PDC (100 mL) in a solution of 30-5 (15g, 24.1mmol) in DCM (13.5g, 26mmol) and _{Ac 2 O (9.8g, 96mmol)} . The mixture was stirred at room temperature for 16 hours. By saturated aqueous NaHCO ₃ The reaction was quenched, followed by extraction with EA. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was dissolved in dry THF (100 mL). To a solution of TMSCCH (12 g, 112 mmol) in THF (200 mL) was added n-BuLi (2.5 N, 44 mL). The mixture was stirred at -78 °C for 15 minutes and at 0 °C for 15 minutes. The mixture was treated with a solution of the crude ketone in THF at -78 ° C and stirred at -30 ° C for 2 hr. By saturated aqueous NH ₄ Cl The reaction was quenched, followed by extraction by EA. The combined the organic layers dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc :EtOAc:

DAST (5.6 g, 35 mmol) was added to a solution of 30-6 (7 g, 7.5 mmol) and pyridine (1.4 g, 17 mmol) in DCM (35 mL). The mixture was stirred at -78 °C for 3 hours. By saturated aqueous NaHCO ₃ The reaction was quenched, followed by extraction with EA. The combined organic layers were dried over anhydrous and concentrated at low pressure. The residue was purified by EtOAc ( EtOAc /EtOAc)

It was stirred at room temperature containing compound 30-7 (4.1g, 5.7mmol) of saturated NH ₃ / MeOH (100mL) 16 hours, and concentrated under low pressure. The residue was redissolved in anhydrous DCM (300mL), and small portions under N ₂ with AgNO ₃ (27.0g, 160mmol), collidine (22mL) and MMTrCl (23.0g, 75.9mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was washed with a saturated NaHCO ₃ and brine. The organic layer was separated, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by a hydrazine column (PE/EA = 10/1) to afford pure intermediate. The intermediate was dissolved in TBAF/THF solution (1 N, 20 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc ( EtOAc:EtOAc

Add imidazole (840 mg, 12 mmol), PPh ₃ (3.2 g, 12 mmol) and I ₂ (2.4 g, 9.2 mmol) to a solution of 30-8 (3.0 g, 4.9 mmol) in THF (50 mL). ). The mixture was stirred at room temperature for 16 hours. By Na ₂ S ₂ O ₃ The reaction was quenched with a saturated aqueous solution, followed by extraction with EA. The combined the organic layers dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc/EtOAc)

To the crude product of 30-9 in anhydrous THF (30mL) was added DBU (2.7g, 18mmol), and heated to 80 ℃. The mixture was stirred for 1 hour and checked by LCMS. The mixture was quenched with water and extracted with EA. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered, and the filtrate was concentrated under a low pressure. The residue was purified by EtOAc (EtOAc/ EtOAc )

NIS (777 mg, 3.5 mmol) and NEt ₃ ̇ 3HF (536 g, 3.3 mmol) were added to ice-cold solution of 30-10 (2.0 g, 3.38 mmol) in dry MeCN (15 mL). The mixture was stirred at room temperature for 16 hours and checked by LCMS. After completion, the mixture was quenched by saturated Na ₂ SO ₃ and sat. NaHCO ₃ and extracted with EA. The organic layer was separated, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

DMAP (490 mg, 4 mmol) and BzCl (580 mg, 4 mmol) were added to a solution of crude product 30-11 (2.1 g, 2. The mixture was stirred overnight and checked by LCMS. The reaction was washed with saturated NaHCO ₃ solution. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc/EtOAc)

To a solution of 30-12 (2.0 g, 2.4 mmol) EtOAc. The mixture was stirred at 110 ° C for 36 hours. The reaction was quenched by water and the mixture was extracted with EA. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc/EtOAc) ESI-MS: m/z 836.11 [M+H] ⁺ .

The mixture was stirred at 30-13 under a N ₂ atmosphere at room temperature (831mg, 1.0mmol) in dry solution (4mL) of n-butylamine in 3 hours. The reaction was monitored by TLC. The solvent was evaporated in vacuo, and by silica gel column (including the DCM MeOH, 0-10%) to afford a crude product was obtained, which was then afford pale pink solid column of silica gel using 30-14 (563mg ).

Imidazole (78.6 mg, 1.16 mmol) and TBSCl (202 mg, 1.34 mmol) were added to a solution of 30-14 (560 mg, 0.89 mmol) in anhydrous pyridine (5 mL). The mixture was stirred at room temperature for 15 hours. The reaction was quenched by the addition of absolute EtOH (0.3 mL). The solution was concentrated to dryness under reduced pressure and co-evaporated three times with toluene. The residue was dissolved in EA (150mL), and the washed with water, washed with saturated NaHCO ₃ and brine. Combined organic layers were dried over Na ₂ SO _4, filtered and evaporated a low pressure. By silica gel column (0-20% EA of hexanes) to afford a white solid was obtained of 30-15 (303mg).

Under N _2, to 30-15 (303mg, 0.41mmol), AgNO 3 (208mg, 1.23 mmol) and collidine (0.55mL, 4.51mmol) in dry DCM was added MMTrCl (4mL) in a solution of (378 mg , 1.3 mmol). At room temperature under N _2, the mixture was stirred overnight and monitored by TLC. The mixture was filtered through a prepacked celite filter, and the filtrate was washed with water and 50% aqueous citric acid and brine. The organic layer was separated, dried over anhydrous Na ₂ SO _4, filtered and concentrated under low pressure. The residue was purified by a hydrazine column (hexanes containing EA, 0% to 30%) to afford 30-16 (374mg, 90%).

At 0 to 5 ℃, to 30-16 (374mg, 0.37mmol) in dry was added a solution of 1.0M TBAF (0.74mL, 0.74mmol) (4mL) in a solution of THF. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with silica gel and filtered. The solvent was evaporated to obtain a crude product, which was (EA of hexane, 0-50%) was purified by silica gel column to obtain 30-17 (265mg).

At 0-5 deg.] C (ice / water bath) was added N- methylimidazole (136μL, 1.66mmol) was stirred in to the 30-17 (187.5mg, 0.16mmol) in dry CH ₃ CN (2.5mL) solution via Then, a solution of (cyclohexyl-L-alanine) phenylphosphonium chlorophosphate (214 mg, 0.62 mmol, dissolved in 0.5 mL of CH ₃ CN) was added. The solution was stirred at room temperature for 3 hours, then diluted with EA then water (15 mL). The solution was washed with H ₂ O, 50% aqueous citric acid and brine. The organic layer was separated, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was silica gel (with zero to 40% EA / hexane) to obtain the (single isomer) 30-18 (108mg). The latter fraction was dissolved to give (the individual isomer) 30-19 (120 mg) as a glassy solid.

Compound 30-18 (108mg, 0.089mmol) was dissolved in anhydrous CH ₃ CN (0.5mL), and was added in dioxane (67μL) 4N HCl at 0 to the 5 ℃ (ice / water bath). The mixture was stirred at room temperature for 40 minutes and anhydrous EtOH (200 μL) was added. The solvent was evaporated at room temperature and co-evaporated 3 times with toluene. The residue was dissolved in _{50% CH 3 CN / H 2} O and purified using acetonitrile and water on a reverse phase HPLC (C18), followed by lyophilization to obtain a compound of a white foam, 30 (26.6mg). ¹ H NMR (CD ₃ OD-d ₄ , 400 MHz) δ 7.89 (s, 1H), 7.33-7.29 (m, 2H), 7.20-7.13 (m, 3H), 7.17 (m, 1H), 6.62 (d, J =15.6 Hz, 1H), 5.39 (t, J = 25.2 Hz, 1H), 4.75-4.42 (m, 6H), 3.92 (t, J = 8.8 Hz, 1H), 3.24 (d, J = 5.6 Hz, 1H), 1.76-1.51 (m, 5H), 1.45-1.25 (m, 12H); ³¹ P NMR (CD ₃ OD-d ₄ ) δ 4.04 (s); ESI-LCMS: m/z = 665.2 [M+ H] ⁺ .

Compound 31 (44.4 mg, individual isomer) was obtained according to the procedure described for compound 30 using 30-19 . ESI-LCMS: m/z =665.15 [M+H] ⁺ .

Example 24

NaH (8.4 g, 0.21 mol) was added to a solution of 3-hydroxypropanenitrile (27 g, 0.15 mol) in THF (150 mL), and the mixture was stirred at room temperature for 1 hour. The compound 10-3 (27 g, 0.03 mol) in THF (100 mL) was treated with this mixture at 0 °C. The combined mixture was stirred at room temperature for 6 hours. The reaction was quenched with H ₂ O, and extracted with EA. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by column chromatography to afford 32-1 ( 9.38 g, 55%).

At room temperature to 32-1 (1g, 1.76mmol) and TsOH (1g, 5.28mmol) in DMF was added 2,2-dimethoxypropane (4mL) and acetone (8 mL) in a solution of (1.8g , 17.6 mmol). The mixture was heated to 50 ° C for 3 hours. The reaction was quenched with H ₂ O (50mL), and extracted with EA (3 × 50mL). Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by column chromatography to afford 32-2 (520g,

TBSCl (53.4 g, 35.6 mmol) was added to a stirred solution of 32-2 (10.0 g, 29.6 mmol) in pyridine (100 mL), and the mixture was stirred for 5 hr. The mixture was concentrated at low pressure and the residue was dissolved in EA (100 mL). Wash the solution with water and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The crude product was co-evaporated 3 times with toluene. Add DMTrCl (2.24 g, 6.65 mmol), 2,4,6-trimethylpyridine (1.07 g, 8.86 mmol) and AgNO _{3 to a} solution of anhydrous crude (2.0 g, 4.43 mmol) in DCM (30 mL) (1.5 g, 8.86 mmol). The mixture was stirred for 1.5 hours. The mixture was filtered and the filtrate was washed with a 0.5N HCl solution. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a low pressure to obtain a yellow solid crude product. The crude product as a yellow solid (7.2g, 10mmol) with the NH ₄ F (7.2g, 200mmol) in MeOH (50mL) was treated in the, and the mixture was heated to 50 deg.] C for 8 hours. Concentrate the mixture at low pressure. The residue was purified by a silica gel column to afford 32-3 (4.8 g, 80%).

TFA ̇Py (40 mg, 0.328 mmol), DMSO (0.15 mL) and DCC (191 mg, 0.99 mmol) were added to a solution of 32-3 (200 mg, 0.33 mmol) in DCM (5 mL). The mixture was stirred for 6 hours and concentrated under reduced pressure. The residue was purified by a hydrazine column to give the product. To a solution of the product (0.2 g, 0.328 mmol) and EtOAc (EtOAc) (EtOAc) The mixture was stirred for 5 hours. Next (, 0.66mmol 24mg) mixture was treated with NaBH _4, and stirred for 3 hours. The mixture was diluted with EA (20 mL) and brine. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by a silica gel column to afford 32-4 (125 mg, 60%).

Pyridine (10 mL) and BzCl (920 mg, 15.6 mmol) were added to a solution of 32-4 (4 g, 6.25 mmol) in DCM (40 mL). The mixture was slowly warmed to room temperature. The reaction was monitored by LCMS. The mixture was quenched with H ₂ O (40mL), and extracted with DCM (3 × 50mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by a silica gel column to afford 32-5 (3. 5 g, 70%).

Add DMTrCl (3.58 g, 11.1 mmol), 2,4,6-trimethyl-pyridine (1.87 g, 15.4 mmol) and AgNO to a solution of 32-5 (5.75 g, 7.7 mmol) in DCM (20 mL) ₃ (2.63 g, 15.4 mmol), and stirred for 3 hours. The mixture was filtered and the filtrate was washed with a 0.5N HCl solution. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by a silica gel column to afford 32-6 (6.25 g, 80%).

NaOMe (0.82 g, 12.6 mmol) was added to a solution of 32-6 (4.3 g, 4. Concentrate the mixture at low pressure. The residue was dissolved in EA (30 mL) and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by a silica gel column to afford 32-7 (2.89 g , 75%).

At -35 ℃, to 32-7 (0.5g, 0.54mmol) and pyridine (0.478g, 5.4mmol) in DCM (4 mL) was slowly added in the solution of Tf ₂ O (0.201g, 0.713mmol) in DCM ( Solution in 3 mL). The mixture was slowly warmed to -5 °C. The reaction was monitored by LCMS. The reaction was, and extracted with DCM (3 × 20mL) saturated with NaHCO ₃ was quenched. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by a hydrazine column to give the product. THF (25 mL, 1 N) containing TBAF was added to the product solution, and the mixture was stirred at room temperature for 5 hr. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to afford 32-8 (221mg, 45%). ESI-MS: m/z 914.4 [M+H] ⁺ .

Compound 32-8 (2.14 g) was dissolved in 80% HCOOH (10 mL) overnight at room temperature. The solvent was evaporated to dryness and the residue was crystallised twice from methanol. The crystals were dissolved in a mixture of THF and 36% HCl 4:1 v/v and kept overnight. The solvent was evaporated and the nucleoside was separated on a Synergy 4 micron Hydro-RP column (Phenominex) by RP HPLC. The dissolution was carried out using a 0 to 60% linear gradient of methanol with 0.1% HCOOH. Compound 32 (370 mg, 48%) was obtained. MS: m/z 316.2 [M-1].

Example 25

A solution of 17-1 (25 mg, 0.04 mmol) in 80% aqueous HCOOH was maintained at room temperature for 3 hours. The mixture was concentrated and co-evaporated with toluene. On silica gel (10g column with _{CH 2 Cl 2 / MeOH (4-10} % gradient)) to obtain the crude residue was purified 17-2 (8mg, 54%).

A mixture of 17-2 (8 mg, 0.02 mmol) in EtOAc (EtOAc) (EtOAc) The reaction was quenched with saturated aqueous NH ₄ Cl, diluted with EtOAc and water. The organic layer was separated and washed with aqueous NaHCO _3, water and brine, and dried (Na ₂ SO _4). On silica gel (10g column with _{CH 2 Cl 2 / i-PrOH} (4-10% gradient)) to obtain the residue was purified compound 17 (9mg, 66%). MS: m/z = 683 [M + 1].

Example 26

Compound 35

At room temperature under N _2, to 32-2 (5.0g, 14.83mmol) in anhydrous pyridine of (50mL) was added TBSCl (3.33g, 22.24mmol) at room temperature. The mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 35-1 (5.69 g, 85.1%).

At room temperature, the PPh ₃ (2.76g, 10.6mmol), and DIAD (2.15g, 10.6mmol) in dioxane was added EtOH (20mL) in a solution of (0.49g, 10.6mmol). After stirring for 30 minutes, a solution of 35-1 (2.4 g, 5.3 mmol) in dioxane (10 mL). The solution was stirred overnight at room temperature. After completion of the reaction, a saturated solution of NaHCO ₃ The reaction was quenched. The solution was extracted with EA (3 x 40 mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

At 0 ℃, under N _2, was added AgNO ₃ (5.67g, 33.4mmol), trimethyl-pyridine in the 35-2 (8g, 16.9mmol) in dichloromethane (60 mL) was carve small parts ( 4.03 g, 33.4 mmol) and MMTrCl (7.7 g, 25 mmol). The mixture was stirred overnight at room temperature. The reaction was monitored by TLC. After completion, the mixture was filtered. _Saturated aqueous filtrate was washed with brine and NaHCO. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc )

Was added to the 35-3 (10g, 13.3mmol) in methanol (100 mL) in a solution of _{NH 4 F (10g, 270mmol)} , and heated to reflux overnight. Concentrate the mixture at low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

At room temperature under N _2, to 35-4 (4g, 6.27mmol) and DCC (3.65g, 18.8mmol) in dry DMSO was added TFA˙Py (40mL) in a solution of (1.21g, 6.27mmol) . The mixture was stirred overnight at room temperature. The reaction was quenched with EtOAc (EtOAc)EtOAc. After filtration, the filtrate was washed with a saturated NaHCO ₃ solution. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue (4 g, 6.27 mmol) was dissolved in dioxane (40 mL) and EtOAc (EtOAc) The mixture was stirred at 30 ° C overnight. NaBH ₄ (0.7 g, 18.9 mmol) was added portionwise at 5 ° C, and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water and EtOAc (3 &lt Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc )

To a solution of 35-5 (2.29 g, 3.43 mmol) in EtOAc (EtOAc) (EtOAc) The mixture was quenched with water and extracted with EtOAc EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by a silica gel column to afford 35-6 (1.62 g, 62%).

At 0 ℃, under N _2, was added to the middle of 35-6 (1.62g, 2.1mmol) in dichloromethane (20mL) was carve small parts of AgNO ₃ (714mg, 4.2mmol), trimethyl pyridine ( 508 mg, 4.2 mmol) and MMTrCl (970 mg, 3.2 mmol). The mixture was stirred overnight at room temperature. The reaction was monitored by TLC. After filtration, _saturated aqueous filtrate was washed with brine and NaHCO. The combined the organic layers dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

(, 2mmol 2.1g) in the in MeOH (30mL) was added at room temperature NaOMe to 35-7 (220mg, 4mmol) and stirred for 1 hour. After TLC indicated complete disappearance of the starting material, the reaction was quenched with dry ice and evaporated at low pressure. The residue was purified by EtOAc EtOAc elut elut elut elut

Tf ₂ O (585 mg, 2.07 mmol) was added dropwise to a solution of 35-8 (1.3 g, 1.38 mmol) EtOAc. The mixture was stirred at room temperature for 3 h and diluted with DCM (150 mL). The solution was washed sequentially with water and brine. The organic solution was dried over Na ₂ SO ₄ and concentrated. The residue (1.48 g) was dissolved in EtOAc EtOAc (EtOAc) The mixture was stirred overnight. The reaction was quenched with saturated aqueous NaHCO _3, and extracted with EA (3 × 60mL). Combined organic layers were dried over Na ₂ SO _4, and the low pressure evaporator. The residue was purified by EtOAc EtOAc (EtOAc) ESI-LCMS: m/z 942.4 [M+H] ⁺ .

Compound 35-9 (0.55 g, 0.58 mmol) was added to ice-cooled 80% aqueous TFA (5 mL) and kept overnight at 5 °C. The mixture was concentrated under reduced pressure at 5 °C. The thick oily residue was co-evaporated several times with toluene and purified on a silica gel (10 g column with CH ₂ Cl ₂ /MeOH (4-15% gradient)) to afford compound 35 (75 mg, 36%). MS: m/z = 358 [M + 1].

Example 27

Compound 36

In the same manner of compound 7, self-contained compound 15 (48mg) of acetonitrile (1.5mL) phosphite with chlorine reagent (0.14 g of) and NMI (0.17mL) Preparation of Compound 36 (8mg, 10%). Purification was carried out by RP-HPLC (30-100% B, A: water containing 50 mM TEAA, B: MeCN containing 50 mM TEAA). MS: m/z = 665 [M-1].

Examples 28

Add a solution of 38-1 (17 g, 65.9 mmol) and 2,2-dimethoxypropane (34.27 g, 329.5 mmol, 5 eq.) in acetone (200 mL) 62.6 mmol, 0.95 equivalents). The mixture was stirred overnight at room temperature. With saturated aqueous NaHCO ₃ The reaction was quenched. The mixture was filtered, and dried over anhydrous Na ₂ SO _4. The filtrate was concentrated to give 38-2 (19 g, 97%).

To 38-2 (6g, 20.1mmol) in anhydrous CH ₃ CN at room temperature (80 mL) was added in the IBX (7.05g, 25.2mmol, 1.25 equiv). The mixture was refluxed for 1 hour and cooled to 0 °C. The precipitate was filtered, and the filtrate was evaporated mjjjjjjjjjj

Compound 38-3 (6 g, 20.1 mmol) was dissolved in 1,4-dioxane (60 mL). 37% HCHO (6 mL, 69 mol) and 2M aqueous NaOH (12 mL, 24 mmol, 1.2 eq. The mixture was stirred at room temperature overnight and neutralized with AcOH to pH = 7. The mixture was treated with NaBH ₄ (1.53g, 40.2mmol, 2 eq) at 10 ℃. The mixture was stirred for 30 min at room temperature, followed by saturated aqueous NH ₄ Cl quenched. The mixture was extracted with EA. Na ₂ SO ₄ organic layers were dried over anhydrous and concentrated to dryness. The residue was purified on a EtOAc EtOAc EtOAc EtOAc .

At -30 ℃, to 38-4 (3.5g, 10.7mmol) in anhydrous pyridine (60 mL) was added dropwise in the containing added DMTrCl (3.6g, 10.7mmol, 1 eq.) Of anhydrous DCM (8mL). The mixture was stirred overnight at room temperature. The solution was treated with MeOH and concentrated to dryness under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

Under N ₂ atmosphere, to 38-5 (2.5g, 4mmol) in dry CH ₂ Cl ₂ (30mL) was added in the AgNO ₃ (0.816g, 4.8mmol, 1.2 equiv), imidazole (0.54g, 8mmol, 2 equivalents) and TBDPSCl (1.18 g, 4.8 mmol, 1.2 equivalents). The mixture was stirred at room temperature for 14 hours. The precipitate was removed by filtration, and the filtrate was washed with brine, and dried over Na ₂ SO _4. The solvent was removed under reduced pressure to give EtOAc m .

Compound 38-6 (4 g, 4.6 mmol) was dissolved in 80% aqueous EtOAc (50 mL). The mixture was stirred at room temperature for 3 hours. The solution was treated with MeOH and concentrated to dryness. The residue was purified by EtOAc EtOAcjjjjjj

Dess-Martin periodinane reagent (1.12 g, 2.65 mmol, 1.5 eq.) was added to a solution of 38-7 (1 g, 1.77 mmol) in anhydrous DCM (15 mL). The reaction was stirred at room temperature for 2.5 hours. By addition of 4% Na ₂ S ₂ O ₃ solution was quenched and washed with 4% aqueous sodium hydrogen carbonate (50mL). The mixture was stirred for another 15 minutes. The organic layer was washed with brine and concentrated. The residue was purified by EtOAc EtOAc EtOAc elut elut elut

To a solution of methyltriphenylphosphonium chloride (2.95 g, 8.51 mmol, 4 eq.) in anhydrous THF (20 mL), EtOAc. 8.1 mmol, 3.8 equivalents). The mixture was stirred at 0 ° C for 1 hour. A solution of 38-8 (1.2 g, 2.13 mmol) in dry THF (3 mL) was then evaporated. The solution was stirred at 0 ° C for 2 hours. With NH ₄ Cl The reaction was quenched and extracted with EtOAc. The organic layer was washed with brine and concentrated. The crude product was purified by EtOAc EtOAc elut elut elut elut

To a solution of 38-9 (0.85 g, 1.43 mmol) in dry THF (50 mL). The mixture was stirred at -70 ° C for 2 hours. With NH ₄ Cl The reaction was quenched and extracted with EtOAc. The organic layer was washed with brine and concentrated. By silica gel column chromatography (20% EtOAc in hexane of) Purification of the crude product was obtained as a white solid of 38-10 (0.4g, 50%).

At room temperature, TPSCl (0.433g, 1.43mmol, 2 eq), DMAP (0.174g, 1.43mmol, 2 to the middle of 38-10 (0.4g, 0.714mmol) in dry CH ₃ CN (30mL) solution of Equivalent) and TEA (1.5 mL). The mixture was stirred at room temperature for 3 hours. NH ₄ OH (3 mL) was added, and the mixture was stirred for 1 hour. The mixture was diluted with EA (150mL), and sequentially washed with water, 0.1M HCl and saturated aqueous NaHCO _3. The organic layer was washed with brine and concentrated. The crude product was purified by EtOAc EtOAc EtOAc elut elut elut

Compound 38-11 (1.35g, 1.5mmol) was dissolved in 80% aqueous (40 mL) in HOAc. The mixture was stirred at 60 ° C for 2 hours and concentrated to dryness. In silica gel column (5% MeOH in the DCM) the crude product was purified on 38 (180mg, 35%) as a white solid of compound. ESI-MS: m/z 282.1 [M+H] ⁺ .

Example 29

At room temperature, TsOH˙H ₂ O (1.35g, 7.1mmol) and trimethoxymethane (8 mL) to cyclopentanone (6.0g, 71mmol) in MeOH (60mL) in the solution. The solution was stirred at room temperature for 2 hours. The reaction was quenched with NaOMe and EtOAc (EtOAc) The organic layer was dried and concentrated to give the crude-1,1-dimethoxycyclopentane (9.2 g), which was dissolved in 1,2-dichloroethane (50 mL). 38-1 (5.0 g, 19.38 mmol) and TsOH ̇H ₂ O (0.36 g, 1.9 mmol) were added to the above solution at room temperature. The mixture was stirred at 60 ° C for 4 hours. The reaction was quenched with TEA and concentrated at low pressure. With the silica gel column (1% MeOH in the DCM) is obtained residue was purified as a white solid of 39-1 (4.77g, 76%).

DMP (6.56 g, 15.6 mmol) was added to a solution of 39-1 (4.77 g, 14.. The solution was stirred at room temperature for 10 hours and concentrated to dryness. The residue was suspended in PE (30 mL) and DCM (5 mL). After filtration, the filtrate was concentrated to give a crude product 39-2 (4.7 g, 100%).

The crude product 39-2 (4.77g, 14.73mmol) was redissolved in dry 1,4-dioxane (50mL) in. A solution of CH ₂ O (37%, 3.6 mL) and aqueous NaOH (2M, 11.3 mL) was then. The mixture was stirred at room temperature for 16 hours. The mixture was treated with NaBH ₄ (1.48g, 40mmol) and stirred at 0 ℃ 0.5 h. The reaction was quenched by water and the mixture was extracted with EA. Na ₂ SO ₄ organic layers were dried over anhydrous and concentrated to dryness. The residue was purified on EtOAc EtOAc (EtOAc)

Tf ₂ O (8.7 g, 31.2 mmol) was added dropwise to a stirred solution of 39-3 (5.0 g, 14.1 mmol) in pyridine (5.6 g, 71 mmol) and DCM (100 mL). The mixture was slowly warmed to 0 ° C and stirred for 2 hours. The mixture was quenched with 0.5 M aqueous HCl and the DCM layer was separated. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated to dryness. The crude product was purified on a silica gel column (PE with 20% EA) to afford 39-4 (4.5 g, 52%).

39-4 (4.5 g, 7.28 mmol) was dissolved in dry THF (50 mL). The solution was partially treated with NaH (60% in mineral oil, 0.32 g, 8 mmol, 1.1 eq.) and the mixture was stirred at room temperature for 8 hr. The reaction was quenched with water and extracted with EtOAc EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a low pressure to obtain a crude product, which was used directly in the next step. To a solution of the crude product (2.0 g, 3.6 mmol) in MeCN (10 mL) The reaction was allowed to proceed overnight. Aqueous NaOH (1 N, ca. 2 eq.) was added and the mixture was stirred 1 hr. The mixture was partitioned between NH ₄ Cl saturated solution and EA. The organic layer was concentrated under reduced EtOAc ( EtOAc m . ESI-MS: m/z 395.0 [M+Na] ⁺ .

Compound 39-6 (3.0 g, 8.06 mmol) was co-evaporated with toluene (30 mL). Add Bz ₂ O (1.82 g, to a solution of 39-6 (3.0 g, 8.06 mmol), DMAP (98 mg, 0.80 mmol) 8.06 mmol) and stirred for 3 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The DCM layer was dried by high vacuum pump to afford crude product 39-7 (3.3 g, 80.9%).

Add TPSCl (507mg, 1.68mmol) in to the ₃ CN (3mL) solution of 39-7 (400mg, 0.84mmol) in dry CH of, TEA (169mg, 1.68mmol) and DMAP (207mg, 1.68mmol), and the chamber The mixture was stirred at room temperature for 2 hours. The completion of the reaction was judged by TLC. An ammonium solution (3.0 mL) was added at room temperature, and the solution was stirred for 2 hours. The mixture was quenched with 1.0 M HCl solution and extracted with DCM. The DCM layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude product was purified by column chromatography to afford 39-8 (250mg, 63%).

Stirred-containing compound 39-8 (250mg, 0.53mmol) at room temperature of 80% formic acid (3mL) for 3 hours. The completion of the reaction was judged by TLC. Concentrate the mixture at low pressure. The crude product was purified by column chromatography to afford 39-9 (130mg, 66%).

Compound 39-9 (270mg, 0.73mmol) was dissolved in MeOH / NH ₃ (10mL), and the solution was stirred for 6 hours. Concentrate the mixture at low pressure. The crude product was washed with DCM, and lyophilized to afford compound 39 (118 mg, 52%). ESI-MS: m/z 328.3 [M+H+Na] ⁺ .

Example 30

Compound 40

Compound 40-1 (3.0 g, 8.42 mmol) was co-evaporated with toluene (30 mL). Add Bz ₂ O (2.01 g, to a solution of 40-1 (3.0 g, 8.42 mmol), DMAP (103 mg, 0.84 mmol) and TEA (2.5 mL, 2 eq. 8.42 mmol) and stirred for 3 hours. The solution was quenched with 1.0 M HCl and extracted with DCM. The DCM layer was dried by high vacuum pump to afford crude product 40-2 (3.3 g, 85%).

To 40-2 (200mg, 0.43mmol) in dry the CH ₃ CN (2mL) was added TPSCl (260mg, 0.86mmol), TEA (95mg, 0.94mmol) and DMAP (106.4mg, 0.86mmol), and in The mixture was stirred at room temperature for 2 hours. The completion of the reaction was judged by TLC. An ammonium solution (1.33 mL) was added at room temperature and stirred for 2 hours. The mixture was washed with 1.0 M HCl solution and extracted with DCM. The DCM layer was dried over anhydrous Na ₂ SO _4, concentrated to dryness and a low pressure. The residue was purified by column chromatography to afford 40-3 (150 mg, 75%).

Compound 40-3 (100 mg, 0.21 mmol) in 80% formic acid (2 mL) was stirred at room temperature for 3 h. The completion of the reaction was judged by TLC. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to afford 40-4 (50mg, 58%).

Compound 40-4 (270mg, 0.68mmol) was dissolved in MeOH / NH ₃ (10mL), and the resulting solution was stirred for 6 hours. Concentrate the mixture at low pressure. The crude product was washed with DCM and lyophilized to give compound 40 (105 mg, 53.8%). ESI-MS: m/z 290.4 [M+H] ⁺ .

Example 31

Compound 41-1 (3.0 g, 8.87 mmol) was co-evaporated with toluene (30 mL). Add Bz ₂ O (2.01 g, to a solution of 41-1 (3.0 g, 8.87 mmol), DMAP (108 mg, 0.88 mmol) and TEA (2.5 mL, 2 eq. 8.87 mmol). The solution was stirred for 3 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The DCM layer was dried by high vacuum vacuum to afford crude product 41-2 (3.5 g, 85%).

To 41-2 (200mg, 0.45mmol) in dry CH TPSCl added in a solution of _{3 CN (2mL) (260mg,} 0.90mmol), TEA (99mg, 0.99mmol) and DMAP (106.4mg, 0.90mmol). The mixture was stirred at room temperature for 2 hours. The completion of the reaction was judged by TLC. An ammonium solution (1.33 mL) was added at room temperature, and the mixture was stirred for 2 hours. The mixture was washed with 1.0 M HCl solution and extracted with DCM. The DCM layer was dried over anhydrous Na ₂ SO _4, concentrated to dryness and a low pressure. The crude product was purified by column chromatography to afford 41-3 (150 mg, 75%).

Compound 41-3 (100 mg, 0.23 mmol) in 80% formic acid (2 mL) was stirred at room temperature for 3 h. The completion of the reaction was judged by TLC. Concentrate the mixture at low pressure. The crude product was purified by column chromatography to afford 41-4 (50mg, 58%).

Compound 41-4 (270mg, 0.72mmol) was dissolved in MeOH / NH ₃ (10mL), and the solution was stirred for 6 hours. Concentrate the mixture at low pressure. The crude product was washed with DCM and lyophilized to give compound 41 (105 mg, 53.8%). ESI-MS: m/z 675.4 [2M+H] ⁺ .

Example 32

To 42-1 (600mg, 1.29mmol) in dry the CH ₃ CN (4mL) was added DMAP (315mg, 2.59mmol), TEA (391mg, 3.87mmol) and TPSCl (782mg, 2.58mmol). The mixture was stirred under N ₂ for 3 hours. Was added a solution of NH ₃ in the THF (2mL), and stirred for 1 hour. With saturated NH ₄ Cl solution The reaction was quenched and extracted with EA. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated to dryness. The residue was purified by EtOAc EtOAc EtOAc :

The compound 42-2 (370 mg, 1.48 mmol) of ammonium methoxide was stirred at room temperature for 4 hours. The solution was concentrated to dryness to afford compound 42 (200 mg, 91%). ESI-MS: m/z 275.9 [M+H] ⁺ .

Example 33

To a solution of bis(isopropoxycarbonyloxymethyl)phosphoric acid triethylammonium (0.6 mmol, prepared from bis(POC) phosphate (0.2 g) and Et ₃ N (83 μL)) in THF was added 43- 1 (74 mg, 0.2 mmol). The mixture was evaporated and made anhydrous by co-evaporation with pyridine followed by toluene. The residue was dissolved in dry THF (2 mL). Diisopropylethylamine (0.35 mL; 10 equivalents) was added followed by BOP-Cl (0.25 g; 5 eq.) and 3-nitro-1,2,4-triazole (0.11 g; 5 eq.). The mixture was stirred at room temperature for 90 minutes, diluted with EtOAc, dried and washed with saturated aqueous NaHCO ₃ and brine, and over Na ₂ SO _4. The residue was purified on a vermiculite (10 g column with CH ₂ Cl ₂ /i-PrOH (4-10% gradient)) to afford 50 mg 43-2 (37%).

A solution of 43-2 (40 mg; 0.06 mmol) in 80% aqueous HCOOH was heated at 45 ° C for 8 hours. The mixture was evaporated, coevaporated with toluene, and the Silica (10g column with _{CH 2 Cl 2 / MeOH (4-10} % gradient)) to afford the 43 (35mg, 91%). MS: m/z = 619 [M + 1].

Example 34

Compound 44-2 was prepared from 40-1 following a similar procedure to Preparation 43-2 . In Silica (10g column, with hexane / EtOAc (35-100% gradient)) to obtain the residue was purified on a 44-2 (0.45g, 75%).

A solution of 44-2 (0.40 g; 0.6 mmol) in 80% aqueous HCOOH (15 mL). The mixture was evaporated, coevaporated with toluene, and the Silica (10g column with _{CH 2 Cl 2 / MeOH (4-10} % gradient)) to afford the 44 (0.27g, 75%). MS: m/z = 603 [M + 1].

Example 35

Compound 45

At 0 ℃, BzCl was added slowly to a 45-1 (3.0g, 4.7mmol) in CH ₃ CN / pyridine (15mL / 20mL) in a solution of (0.67g, 4.7mmol). The mixture was stirred at 10 ° C for 12 hours. The reaction was quenched with saturated NaHCO ₃ solution and extracted with DCM. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a EtOAc EtOAc ( EtOAc :EtOAc:

To a solution of 45-2 (1.0 g, 1.35 mmol) in EtOAc (EtOAc) The mixture was stirred overnight at 20-35 °C. The reaction was monitored by LCMS and TLC. The reaction was quenched with MeOH and concentrated EtOAc. The residue was purified by EtOAc EtOAc (EtOAc):

Was added to the 45-3 (1.5g, 1.35mmol) in of MeOH / THF (1 / 1,10mL) solution of NaOMe (0.11g, 2.0mmol), and stirred at 40 ℃ 3 hours. The reaction was monitored by TLC. The reaction was quenched with dry ice and concentrated to dryness. The residue was dissolved in DCM (100 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (PE containing EA, 2% to 50%) to afford 45-4 (1.0 g, 79%).

Pyridine (241 mg, 3.05 mmol) and Tf ₂ O (344 mg, 1.22 mmol) were slowly added to a solution of 45-4 (950 mg, 1.02 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 12 hours. The completion of the reaction was judged by TLC and LCMS. Reaction was quenched with a saturated solution of NaHCO _3, and extracted with DCM (3 × 60mL). The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated to a low pressure to obtain a crude product 45-5 (1.08g, 1.02mmol), which was used without further purification.

TBAF (0.8 g, 3 mmol) was added to a solution of 45-5 (1.08 g, 1.02 mmol) in THF (6 mL) and stirred at 30-40 ° C for 12 hours. The reaction was quenched with saturated NaHCO ₃ solution, and extracted with EA (3 × 60mL). Na ₂ SO ₄ solution was dried over anhydrous, low-pressure concentrated. The residue was purified by a silica gel column (2% to 50% of EA of PE) to afford 45-6 (0.62 g, 65%).

A mixture of 45-6 (0.55 g, 0.59 mmol) in TFA (90%, 5 mL) was stirred at 50-60 ° C for 16 h. The mixture was treated with MeOH and concentrated at low pressure. The residue was purified by preparative HPLC to afford compound 45 (60 mg, 31%). ESI-MS: m/z 324.0 [M+H] ⁺ .

Example 36

Compound 46

Add 46-1 (91 mg, 0.11) to a solution of bis(isopropoxycarbonyloxymethyl)phosphoric acid triethylammonium (0.33 mmol, prepared from 110 mg of bis(POC) phosphate and 46 μL of Et ₃ N) in THF. Mm). The mixture was evaporated and made anhydrous by co-evaporation with pyridine followed by toluene. The residue was dissolved in dry THF (1.5 mL) and evaporated. Diisopropylethylamine (0.19 mL, 10 eq.) was added followed by BOP-Cl (0.14 g, 5 eq.) and 3-nitro-1,2,4-triazole (63 mg, 5 eq.). The mixture was stirred at 0 ℃ 90 min, diluted with EtOAc (30mL), washed with saturated aqueous NaHCO _3, brine and dried (Na ₂ SO _4). The residue was purified on a vermiculite (10 g column with CH ₂ Cl ₂ /i-PrOH solvent system (2-10% gradient)) to afford 46-2 (13 mg, 10%) and 46-3 (95 mg, 58%) ).

A solution of 46-2 and 46-3 (13 mg and 95 mg, respectively) in 80% aqueous HCOOH (3 mL) was stirred at room temperature for 3 hr, then evaporated and evaporated. In Silica (10g column with _{CH 2 Cl 2 / MeOH (4-10} % gradient)) obtained residue was purified (42mg, 94%) yield of compound 46. MS: m/z = 628 [M + 1].

Example 37

Compound 47-1 (320mg, 0.51mmol) was dissolved in (7 mL) of a mixture of _{CH 3 COOH / THF / H 2} O (4/2/1) and stirred at 50 deg.] C for 2 hours. The solution was concentrated to dryness, and the residue was purified by preparative HPLC by was obtained as a white solid of compound 47 (38mg, 31%). ESI-MS: m / z 296.9 [M + H + Na] +.

Example 38

TIPDSCl (54.98 g, 174 mmol) was added portionwise to a stirred solution of 48-1 (30.0 g, 116 mmol) EtOAc. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water and concentrated to dryness. The residue was diluted with EA and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated at low pressure. The residue was purified on a silica gel column (PE with 50% EA) to afford 48-2 (58 g, 99%).

DHP (33.6 g, 400 mmol) and TFA (6.84 g, 60 mmol) were added dropwise to a stirred solution of 48-2 (20.0 g, 40 mmol) in anhydrous DCM (200 mL). The mixture was stirred at room temperature for 16 hours. The solution was adjusted to pH = 8 by the addition of 2N NaOH solution. , And extracted with DCM (100mL) the mixture was washed with saturated aqueous NaHCO _3. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified on a silica gel column (20% EtOAc ) to afford 48-3 (16 g, 68%).

To 48-3 (41g, 70mmol) in dry MeOH was added _{NH 4 F (51.88g, 140mmol)} (400mL) in the solution. The mixture was refluxed for 1 hour and then concentrated in vacuo. The residue was purified on a EtOAc EtOAc EtOAc (EtOAc)

Imidazole (6.89 g, 101.32 mmol) and TBSCl (10.92 g, 74.29 mmol) were added portionwise to a stirred solution of 48-4 (23.1 g, 67.54 mmol) in anhydrous pyridine (200 mL). The mixture was stirred at room temperature for 16 hours. The solution was quenched with water and concentrated to dryness. The residue was diluted with EA and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column to afford 48-5 (23 g, 74%).

At 0 ℃, under N _2, to 48-5 (27.56g, 60.44mmol) in dry MeCN (560mL) was added DMAP (18.43g, 151.1mol) and PhOCSCl (14.55g, 84.61mmol) in the solution. The mixture was stirred at room temperature overnight and the reaction was quenched with water. The mixture was extracted with EA. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (solvent eluting with 30% EA) to afford 48-6 (23 g, 64%).

A solution of AIBN (1.21 g, 7.3 mmol) and Bu ₃ SnH (10.73 g, 36.74 mmol) in toluene (10 mL) was added to a solution of 48-6 (14.5 g, 24.5 mmol). N _{2 was} bubbled through the solution for 30 minutes. The mixture was allowed to warm to 135 ° C for 2 hours. A saturated aqueous solution of CsF was added, and the mixture was stirred for 1 hour. The mixture was diluted with EA (150mL), and washed sequentially with water, washed with saturated aqueous NaHCO ₃ and brine. The organic layer is removed at low pressure. The residue was purified on a silica gel column (PE containing 30% EA) to afford 48-7 (10.5 g, 97%).

To 48-7 (21g, 47.73mmol) in dry MeOH was added _{NH 4 F (35.32g, 950mmol)} (200mL) in the solution. The mixture was refluxed for 1 h and concentrated in vacuo. The residue was purified on a silica gel column (20% MeOH EtOAc ) to afford 48-8 (14 g, 90%).

At room temperature under N ₂ atmosphere, TFA˙Py (2.37g, 12.27mmol) was added to the 48-8 (4g, 12.27mmol) and DCC (7.58g, 36.81mmol) in dry DMSO (40mL) in the In the mixture. The mixture was stirred at room temperature for 2 hours. 37% formaldehyde (10 mL, 115 mmol) was added at room temperature and stirred for 15 min then was treated with 2N NaOH (20 mL, 40 mmol). The mixture was stirred at 30 ° C overnight and neutralized with AcOH to pH = 7. NaBH ₄ (1.87 g, 49.08 mmol) was added portionwise at 5 ° C, and the mixture was stirred at room temperature for 30 min. The mixture was extracted with EtOAc (3×100 mL). Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc )

At 0 ℃, under N _2, (, 5.62mmol 2g) in of anhydrous CH ₃ CN (8mL) containing pyridine was added 48-9 (10mL) and BzCl (0.79g, 5.62mmol) in DCM of (2mL). The mixture was stirred overnight at room temperature. The reaction was quenched with water and concentrated at low pressure. The residue was diluted with EA (50 mL) and washed sequentially with water and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified on a silica gel column ( EtOAc EtOAc EtOAc )

At 0 ℃, under N _2, to 48-10 (1.6g, 3.48mmol) in dry pyridine (16 mL) was added in the MMTrCl (1.61g, 5.22mmol). The mixture was stirred overnight at room temperature. The reaction was quenched with water and concentrated in vacuo. The residue was diluted with EA (50 mL) and washed sequentially with water and brine. The organic layer was dried over Na ₂ SO ₄ dried, and concentrated to a low pressure to obtain a crude product was 48-11 (2.55g, 100%), which was used without further purification.

To 48-11 (2.55g, 3.48mmol) in dry MeOH (50mL) was added in the NaOCH ₃ (0.28g, 5.23mmol). The mixture was stirred at 45 ° C for 2 hours, by bubbling with dry ice until pH = 7 and concentrated to dryness. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc )

Pyridine (1.17 g, 14.8 mmol) was added to a solution of 48-12 (0.93 g, 1.48 mmol) in dry. DCM (3 mL) containing Tf ₂ O (0.63 g, 2.22 mmol) was added dropwise. The mixture was stirred at -30 ° C to 0 ° C for 20 minutes and at 0 ° C for 10 minutes. The reaction was quenched with water and EtOAc EtOAc m. Na ₂ SO ₄ anhydrous organic layer was dried and concentrated to a low pressure to obtain a crude product was 48-13 (1.13g, 100%), which was used without further purification.

TBAF (3.86 g, 14.8 mmol) was added to a solution of 48-13 (1.13 g, 1.48 mmol) in dry THF (10 mL). The mixture was stirred at 30 ° C for 2 hours. The reaction was quenched with water and EtOAc (EtOAc &lt Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated to dryness. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc :EtOAc

At room temperature, (50mg, 0.079mmol) in of anhydrous CH ₃ CN (1mL) was added TPSCl (48.07mg, 0.16mmol), DMAP (19.36mg, 0.16mmol) and NEt ₃ (0.2 to 47-1 mL). The mixture was stirred at room temperature for 3 hours. 28% aqueous ammonia (0.4 mL) was added, and the mixture was stirred for 1 hour. The mixture was diluted with EA (150mL), and washed sequentially with water, washed with saturated aqueous NaHCO ₃ and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc )

Compound 48-14 (320 mg, 0.51 mmol) was dissolved in 80% HCOOH (6 mL), and the mixture was stirred at 10 ° C for 1 hour. The mixture was concentrated low pressure, and the residue was purified by preparative HPLC by was obtained as a white solid of compound 48 (43mg, 31%). ESI- MS: m / z 273.9 [ M + H] +, 547.1 [2M + H] +.

Example 39

Imidazole (19.1 g, 280 mmol) and TBSCl (42.1 g, 281 mmol) were added to a solution of 49-1 (20.0 g, 70.2 mmol) in anhydrous pyridine (200 mL). The solution was stirred at 25 ° C for 15 hours, then concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc then filtered. The filtrate was concentrated to dryness to give a TBS-protected derivative (36.4 g, 99%). The TBS protected derivative (36.5 g, 71.1 mmol) was dissolved in THF (150 mL). H ₂ O (100 mL) was added followed by AcOH (300 mL). The solution was stirred at 80 ° C for 13 hours. The reaction was cooled to room temperature and then was concentrated under reduced pressure to dryness to obtain 49-2 (31.2g, 61%) of a white solid.

Was added to the 49-2 (31.2g, 78.2mmol) in dry pyridine (300 mL) in a solution of _{Ac 2 O (11.9g, 117.3mmol)} . The mixture was stirred at 25 ° C for 18 hours. MMTrCl (72.3 g, 234.6 mmol) and AgNO ₃ (39.9 g, 234.6 mmol) were added, and the solution was stirred at 25 ° C for 15 hours. The H ₂ O quenched reaction was added and the solution was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give a crystallitelitelitelitelitelitelitelitelitelitelitelitelite MMTr protected derivative of the amine (35.2g, 49.3mmol) was dissolved in NH ₃ / MeOH (300mL) in. The mixture was stirred at 25 ° C for 20 hours. The solution was evaporated to dryness and purified EtOAc EtOAcjjjjjjj

Dess-Martin periodinane (11.3 g, 26.8 mmol) was added to a solution of 49-3 (12.0 g, 17.9 mmol) in anhydrous DCM (200 mL). The mixture was stirred at 0 ° C for 2 hours, followed by stirring at room temperature for 2 hours. The mixture was quenched with saturated NaHCO ₃ and Na ₂ S ₂ O ₃ solution. The organic layer was washed with brine (2 ×) and was washed and dried over anhydrous Na ₂ SO _4. Evaporation of the solvent gave the aldehyde (12.6 g) which was used directly in the next step. To a solution of the aldehyde (12.6 g, 18.0 mmol) in 1,4-dioxane (120 mL) was added 37% EtOAc (11.6 g, 144 mmol) and 2N aqueous NaOH (13.5 mL, 27 mmol). The mixture was stirred at 25 ° C overnight. Add EtOH (60mL) and NaBH ₄ (10.9g, 288mmol), and the reaction was stirred for 30 min. With saturated aqueous NH ₄ Cl was quenched mixture was then extracted with EA. The organic layer was dried over Na ₂ SO _4, and by silica gel column chromatography (DCM: MeOH = 200: 1 to 50: 1) to obtain the form of 49-4 (7.5g, 59%) of a yellow solid.

At 0 ℃, was added in the pyridine 49-4 (3.8g, 5.4mmol) in DCM (40mL) solution (10 mL) and DMTrCl (1.8g, 5.4mmol). The solution was stirred at 25 ° C for 1 hour. MeOH (15 mL) was added and the solution was concentrated. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc MMTr protected derivative of the (3.6g, 3.6mmol) in dry pyridine (30mL) was added in the TBDPSCl (2.96g, 10.8mmol) and AgNO ₃ (1.84g, 10.8mmol). The mixture was stirred at 25 ° C for 15 hours. Filter and concentrate the mixture. The mixture was dissolved in EtOAc and washed with brine. The organic layer was dried over Na ₂ SO _4, followed by silica gel column chromatography (DCM: MeOH = 200: 1 to 50: 1) to obtain the solid form of a protected derivative of TBDPS (3.8g, 85.1%). Protection of the TBDPS derivative (3.6g, 2.9mmol) in dry DCM (50mL) was added in the containing Cl ₂ CHCOOH (1.8mL) of dry DCM (18mL). The mixture was stirred at -78 ° C for 1 hour. Cl ₂ CHCOOH (3.6 mL) was added at -78 °C. The mixture was stirred at -10 ° C for 30 minutes. The mixture was quenched with saturated aqueous NaHCO _3, and extracted with DCM. The organic layer was dried over Na ₂ SO _4, followed by silica gel column chromatography (DCM: MeOH = 200: 1 to 50: 1) to afford 49-5 (2.2g, 80%).

In the to 49-5 (800mg, 0.85mmol) in dry DCM (20mL) was added dropwise a solution of ice-cold pyridine (336mg, 4.25mmol) and _{Tf 2 O (360mg, 1.28mmol)} . The reaction mixture was stirred at 0 °C for 15 minutes. The reaction was quenched with ice water and stirred for 30 min. The mixture was extracted with EtOAc, washed with brine (50mL), and dried over MgSO _4. The solvent was evaporated to give the crude bis(trifluoromethanesulfonate) derivative. To a solution containing bis(trifluoromethanesulfonate) (790 mg, 0.73 mmol) in dry DMF (35 mL). The mixture was heated to 40 ° C and stirred overnight. The completion of the reaction was judged by LCMS. The solution was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO ₄ were combined and dried, and the silica gel column (DCM / MeOH = 100: 1 ) obtained residue was purified 49-6 (430mg, 61%).

In MeOH was added to the 49-6 (470mg, 0.49mmol) of (85 mL) in _{NH 4 F (8.1g, 5.92mmol)} , and the solution was heated to reflux overnight. The mixture was filtered and the filtrate was concentrated to dry. The residue was purified on EtOAc EtOAc (EtOAc:EtOAc: The diol (130 mg, 0.21 mmol) in formic acid (5 ml) was stirred overnight at 25 °C. The solution was concentrated to dryness and MeOH (30 mL) The completion of the reaction was judged by LCMS and HPLC. The solvent was removed, and the compound was obtained as a white solid of the crude product was washed with EtOAc 49 (58mg, 81%) . ESI-MS: m/z 333.8 [M+H] ⁺ , 666.6 [2M+H] ⁺ .

Example 40

Compound 50

Compound 50-1 (5.0 g, 8.5 mmol) and 6-chloroindole (3.0 g, 17.7 mmol) were co-evaporated three times with anhydrous toluene. DBU (7.5 g, 49 mmol) was added to a stirred suspension (50 mL) of 50-1 and EtOAc. The mixture was stirred at 0 °C for 15 minutes, and TMSOTf (15 g, 67.6 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 ° C for 15 minutes until a clear solution formed. The mixture was heated to 70 ° C and stirred overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature and diluted with EA (100 mL). The solution was washed with a saturated solution of NaHCO ₃ and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified on a silica gel column ( EtOAc EtOAc EtOAc: EtOAc :

At 40 to 60 ℃, in an autoclave, containing NH MeOH ₃ of the (8N, 20mL) treating compound 50-2 (3.0g, 4.8mmol) for 12 hours. The mixture was evaporated under reduced pressure and the residue was purified mjjjjjjjjjjjjjjj

Add TsOH ̇H ₂ O (8.4 g, 0.044 mol) and 2,2-dimethoxypropane to a solution of 50-3 (4.3 g, 14.8 mmol) in acetone/DMF (4/1, 40 mL). 30 g, 0.296 mol), and the mixture was stirred at 60 to 70 ° C for 12 hours. The mixture was concentrated at low pressure and the residue was purified on a silica gel column (PE from EA, 50% to 100%) to afford 50-4 (5.0 g, 83%).

TBSCl (5.3 g, 34.9 mmol) was added to a solution of 50-4 (10.5 g, 31.7 mmol) in pyridine (50 mL), and the mixture was stirred at room temperature for 12 hr. The solvent was removed at low pressure and the residue was dissolved in DCM (100 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Compound 50-5 (8.4 g, 18.8 mmol) was co-evaporated with pyridine. MMTrCl (8.1 g, 26.4 mmol) was added to a stirred solution of 50-5 (8.4 g, 18.8 mmol) in pyridine (35 mL). The mixture was stirred at 30 to 40 ° C for 12 hours under N ₂ . The mixture was concentrated under reduced pressure and the residue was crystalljjjjjjj The solution was washed with a saturated solution of NaHCO _{3, 2} SO ₄ dried and concentrated to a low pressure over anhydrous Na. The residue was purified on a silica gel column ( EtOAc EtOAc ( EtOAc: EtOAc )

TBAF (4.62 g, 0.018 mol) was added to a solution of 50-6 (11.5 g, 0.016 mol) in THF (100 mL), and the mixture was stirred for 4 hr. The solvent was evaporated at low pressure and the mixture was dissolved in DCM (150 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (PE containing EA, 50% to 100%) to afford 50-7 (8.8 g, 91%). ESI-MS: m/z 604.4 [M+H] ⁺ .

Add DCC (4.5 g, 21.9 mmol), DMSO (2.5 mL), TFA ̇Py (1.48 g, to a solution of 50-7 (4.4 g, 7.3 mmol) in dioxane (50 mL). 7.65 mmol). The mixture was slowly warmed to room temperature and stirred for 4 hours. The completion of the reaction was judged by LCMS. Concentrate the mixture at low pressure. The residue was purified on EtOAc EtOAc EtOAc (EtOAc)

Water (20 mL), HCHO (37%, 7 mL) and NaOH (1N, 15 mL) were added to a solution of 50-8 in dioxane (40 mL). The solution was stirred overnight at room temperature. The mixture was slowly treated with NaBH ₄ (1.1g, 29.2mmol), and stirred for 30 minutes. The mixture was adjusted to pH = 7-8 by slowly adding HCl (1M) solution and extracted with EA (150 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column to afford 45-1 (3.0 g, 65%). ESI-MS: m/z 633.9 [M+H] ⁺ .

DMTrCl (3.6 g, 10.7 mmol) was added to a solution of 45-1 (1.5 g, 2.37 mmol) in anhydrous pyridine (30 mL). The mixture was stirred overnight at room temperature. The solution was quenched with MeOH and concentrated EtOAc. The residue was purified by column chromatography eluting elut elut elut elut elut elut

To a solution of 50-9 (1.1 g, 1.18 mmol) in EtOAc (10 mL), EtOAc (EtOAc (EtOAc) The mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in EA (50 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (PE containing 30% EA) to afford 50-10 (0.83 g, 67%).

At -70 ℃, added to the sum 50-10 (1.1g, 1.05mmol) in DCM (12mL) solution of Cl ₂ CHCOOH (0.5mL) and stirred for 1 hour. DCM containing Cl ₂ CHCOOH at -70 deg.] C (1 mL) of (10 mL) was treated, and the mixture was stirred at -70 to -10 ℃ 20 minutes. The completion of the reaction was judged by LCMS. Reaction was quenched with a saturated solution of NaHCO _3, and extracted with DCM (3 × 40mL). The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (PE containing EA, 15% to 30%) to afford 50-11 (0.58 g, 74%).

Tf ₂ O (90 mg, 0.32 mmol) was added to a solution of 50-11 (200 mg, 0.268 mmol) and pyridine (53 mg, 0.67 mmol) in anhydrous DCM (5 mL). The mixture was stirred for 1 hour and slowly warmed to room temperature. The completion of the reaction was judged by TLC. Reaction was quenched with a saturated solution of NaHCO _3, and extracted with DCM (3 × 30mL). The organic phase was dried over anhydrous Na ₂ SO _4, concentrated to dryness and a low pressure. The crude product 50-12 (200 mg, 0.27 mmol) was used without further purification.

To a solution of 50-12 (200 mg, 0.27 mmol) in EtOAc (5 mL) The solvent was evaporated <RTI ID=0.0> The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The crude product 50-13 was used without further purification.

A mixture of 50-13 (245 mg, 0.32 mmol) and TBAF (200 mg, 0.7 mmol) in THF was stirred at 30 ° C for one hour. The mixture was concentrated under reduced pressure and the residue was crystalljjjjjjjj The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (PE containing EA, 2% to 50%) to afford 50-14 (150 mg, 72%). ESI-MS: m/z 652.3 [M+H] ⁺ .

Compound 50-14 (0.2 mmol) was dissolved in methanol containing 50% TFA (10 mL) and mixture was maintained at room temperature overnight. The solvent was evaporated and co-evaporated with a methanol/toluene mixture to remove traces of acid. The residue was dissolved in methanol containing 20% triethylamine for 15 min and evaporated. The product was isolated by RP HPLC on a Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of 0 to 60% methanol in 50 mM triethylammonium acetate buffer (pH 7.5) was used to dissolve. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess buffer. Compound 50 (45 mg, 67%) was obtained. MS: m/z 338.0 [M-1].

Example 41

Compound 51

NaH (800 mg, 20 mmol) was added to a solution of 51-1 (12.3 g, 19.9 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was treated with CsF (30.4 g, 200 mmol) and then stirred at room temperature for 3 hr. The reaction was quenched with water and extracted with EtOAc. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated to dryness. The residue was purified on a EtOAc EtOAc (EtOAc:EtOAc)

A solution of 51-2 (4.1 g, 12.1 mmol) in THF (120 mL) was added EtOAc (1 N, 13 mL). The mixture was stirred at room temperature for 3 hours. The solution was neutralized to a pH of about 7 with 0.5 M aqueous HCl. The mixture was partitioned between EA and water. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated to dryness. The residue was purified on a EtOAc EtOAc EtOAc (EtOAc) ESI-MS: m/z 379.1 [M+Na] ⁺ .

Compound 51-3 (0.2 mmol) was dissolved in 80% HCOOH (10 mL), and the mixture was warmed at 45 ° C for 24 hr. The solvent was evaporated and co-evaporated with a methanol/toluene mixture to remove traces of acid. The residue was dissolved in methanol containing 20% triethylamine for 15 min and evaporated. Compound 51 (68%) was isolated by silica gel chromatography (methanol gradient from 5% to 20% in DCM). MS: m/z 289.0 [M-1].

Example 42

Compound 52

A mixture of 52-2 (1.2 g; 4 mmol) and Na.sub.1 (0.6 g; 4 mmol) Compound 52-1 (1 g; 3 mmol) and K ₂ CO ₃ (2.07 g; 45 mmol) were added. The mixture was stirred at room temperature for 24 hours. The precipitate was filtered and the filtrate was evaporated. In Silica (25g column, with hexane / EtOAc (30-100% gradient)) to obtain the residue was purified on a colorless foam of 52-3 (1.14g; 64%).

Add 52 to the bis (isopropoxy-carbonyloxy-methyl) triethylammonium phosphate (2.3mmol, and Et ₃ N (0.32mL) was prepared from bis (POC) phosphate (0.75 g of)) solution in THF of -3 (1.14 g; 1.9 mmol). The mixture was evaporated and made anhydrous by co-evaporation with pyridine followed by toluene. The residue was dissolved in dry THF (20 mL) andEtOAc. Diisopropylethylamine (1.0 mL; 2 equivalents) was added followed by BOP-Cl (0.72 g; 1.5 eq.) and 3-nitro-1,2,4-triazole (0.32 g; 1.5 eq.). The mixture was stirred at 0 ℃ 90 minutes, diluted with EtOAc, washed with saturated aqueous NaHCO ₃ and brine, and dried (Na ₂ SO _4). The residue was purified on a vermiculite (25 g column with CH ₂ Cl ₂ /i-PrOH (3-10% gradient)) to afford 52-4 (1.2 g, 70%).

A solution of 52-4 (1.2 g; 1.3 mmol) in 80% aqueous HCOOH was stirred at room temperature for 2 hr then concentrated. The residue with toluene, and then co-evaporated with MeOH containing a small amount of Et ₃ N (2 drops) of. Purification on a vermiculite (25 g column with CH ₂ Cl ₂ /i-PrOH (4-10% gradient)) afforded 52-5 (0.96 g, 85%).

To a solution of 52-5 (0.52 g; 0.57 mmol) in Et.sub.2 (25 mL), HCl (4N / dioxane; 0.29 mL, 2 eq.) and 10% Pd/C (25 mg). The mixture was stirred under H ₂ (normal pressure) for 1 hour. The catalyst was removed by filtration through a pad of Celite, and filtrate was evaporated to afford compound 52 (4.2 g; MS: m/z = 732 [M + 1].

Example 43

Following the procedure of Preparation 52-4 , from 53-1 (0.16 g; 0.49 mmol) and bis(isopropoxycarbonyloxymethyl)triethylammonium (0.74 mmol) and DIPEA (0.34 mL) Compound 53-2 (0.20 g, 64%) was obtained from EtOAc (EtOAc) (EtOAc)

A solution of 53-2 (0.20 g; 0.31 mmol) in 80% aqueous HCOOH was stirred at room temperature for 2 hr then concentrated. The residue with toluene, and then co-evaporated with MeOH containing a small amount of Et ₃ N (2 drops) of. Purification on silica gel (10 g column with CH ₂ Cl ₂ /MeOH (4-10% gradient)) followed by 250 x 30 mm (Phenomenex P/N 00G-4375-U0-AX) on a Synergi Hydro RP column The RP-HPLC was purified 5 times using H ₂ O and ACN, both 50 mM TEAA. The gradient was 25-75% ACN in 24 minutes, 24 mL/min, 254 nM detection. The product was dissolved at 16.0 minutes. Convergence and lyophilization of pure soluble fractions. By product was dissolved in DMSO (2mL) and the product was injected into the column using only the same H ₂ O and ACN removed up of TEAA. Concentration and lyophilization of the pure fractions gave compound 53 (18 mg). MS: m/z = 1197 [2M + 1].

Example 44

To the ice-cold solution of 2-methoxyethanol (97 mmol, 7.7 mL) in dichloromethane (EtOAc) (EtOAc) (EtOAc) mL). After stirring overnight at room temperature, the mixture was washed twice with 0.5 M HCl then washed with water and aqueous sodium hydrogen carbonate. The mixture was dried over magnesium sulfate, filtered, evaporated in vacuo and vacuum distilled to obtain a colorless oil of 54-2 (13.0g).

Compound 54-2 (5.7 g) was added to a solution of sodium iodide (21.07 g) in acetone (45 mL). After stirring at 40 ° C for 2.5 hours, the mixture was cooled in ice, filtered and evaporated in vacuo. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and sodium thiosulfate, dried over magnesium sulfate, filtered and evaporated in vacuo to obtain a light yellow oil of 54-3 (8.5g), which was used without further It can be used after purification.

A mixture of phosphoric acid (crystals, 2.4 g) and triethylamine (6.6 mL) in benzyl alcohol (13 g; 12.5 mL) was stirred at room temperature until the phosphoric acid was completely dissolved. Trichloroacetonitrile (17.2 g; 11.94 mL) was added, and the mixture was stirred at room temperature for 18 hr. The solvent and excess trichloroacetonitrile were removed under reduced pressure. The residue was dissolved in water (ca. 200 mL) and aqueous was washed with ether (3×50 mL). After lyophilization, benzylphosphoric acid (triethylamine salt) (7.15 g) was obtained as a pale yellow semi solid. A solution of benzylphosphoric acid (TEA salt, 1.6 g) in MeOH (90 mL) and water (30 mL). The resin was removed by filtration, and silver carbonate powder (1.25 g) was added to the filtrate. After heating the suspension at 80 ° C for 1 hour, all the solvent was removed under reduced pressure to dryness. The solid was used without further purification.

To the benzylphosphoric acid (silver salt) was added anhydrous acetonitrile (25 mL) followed by 54-3 (3.12 g; 12 mmol). The suspension was stirred overnight at room temperature. After the solid was removed by filtration, EtOAc/EtOAc (3:1 v/v) was used to elute the product to afford product 54-4 (860 mg, 50%).

Compound 54-4 (750 mg; 1.65 mmol) was dissolved in methanol (10 mL). Palladium on carbon (85 mg) and TEA (1 equivalent) were added. The flask was charged with hydrogen for 1 hour. The catalyst was filtered and the solvent was evaporated in vacuo to afford EtOAc (EtOAc)

Compound 54-6 (320 mg; 0.9 mmol) and 54-5 (510 mg, 1.35 mmol; 1.5×) were co-evaporated twice with pyridine and twice with toluene. Compounds 54-5 and 54-6 were dissolved in THF (8 mL) at 0 °C. Add diisopropylethylamine (DIPEA) (0.62 mL; 4 equivalents), bis(2-di- oxy-3-oxazolidinyl)phosphinium chloride (Bop-Cl) (0.45 g; 2 equivalents) Nitrotriazole (0.2 g, 2 equivalents). The mixture was kept at 0 °C for 2 hours then diluted with EA (50 mL). The mixture was extracted with saturated sodium bicarbonate (2×50 mL) and dried over sodium sulfate. The organic solvent was removed in vacuo. By flash chromatography using hexane in a gradient of 10 to 100% of the EA was obtained residue was purified by purified 54-7 (430mg, 0.6mmol).

Purified 54-7 was dissolved in 80% aqueous HCOOH (20 mL) and kept at 45 °C for 18 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was co-evaporated with toluene (3 x 25 mL). By flash chromatography using DCM and 0-20% gradient of methanol in the residue obtained was purified compound 54 (200mg, 0.3mmol). ¹ H-NMR (CDCl ₃ ): δ 9.28 (s, 1H), 7.54 (d, 1H), 5.95 (s, 1H), 5.65-5.81 (m, 5H), (d, 2H), 4.76 (dd, 2H), 4.44-4.46 (m, 1H), 4.35-4.40 (m, 5H), 4.22 (2H), 4.04 (1H), 3.65 (t, 4H), 3.39 (6H), 1.8 (s, 1H), 1.24(s, 3H). ³¹ P-NMR (CDCl ₃ ): δ -4.09 ppm.

Example 45

From 55-1 (0.21 g; 0.35 mmol) and bis(isopropoxycarbonyloxymethyl)triethylammonium phosphate (0.54 mmol) with DIPEA (0.18 mL), BopCl (178 mg) and 3-nitro- Compound 55-2 (158 mg, 50%) was obtained from THF (4 mL) elute

A solution of 55-2 (158 mg) in acetonitrile (1 mL) and HCl (4N / dioxane; The reaction was quenched with MeOH and concentrated. On silica gel (10g column with _{CH 2 Cl 2 / i-PrOH} (3-10% gradient)) obtained residue was purified compound 55 (85 mg, 76%) a. MS: m/z = 656 [M + 1].

Example 46

Tf ₂ O (136 mg, 0.48 mol) in DCM (1 mL) was added dropwise to a solution of 49-3 (300 mg, 0.4 mmol) and pyridine (80 mg, 1.0 mmol) in DCM (5 mL) Solution in the middle. The mixture was stirred at -30 ° C to 0 ° C for 20 minutes. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous Na ₂ SO _4, and evaporated to afford crude product 56-1 (352.8mg, 0.4mmol), which was used without further purification.

To a solution of 56-1 (352.8 mg, 0.4 mmol) in DMF (5 mL) The mixture was stirred at 30 ° C for 10 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous Na ₂ SO _4, concentrated to dryness and a low pressure. The residue was purified by preparative TLC ( EtOAc EtOAc EtOAc )

A solution of AIBN (34 mg, 0.21 mmol) and Bu ₃ SnH (307.7 mg, 1.05 mmol) in toluene (10 mL) was added to a solution of 56-2 (600 mg, 0.7 mmol). The mixture was bubbled with N ₂ for 30 minutes and heated to 135 deg.] C for 2 hours. The mixture was treated with a saturated aqueous solution of CsF and then stirred for 2 hr. The mixture was diluted with EA (100 mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (PE containing 10% EA) to afford 56-3 and sub-products (400 mg, 72%).

A mixture of 56-3 (400 mg, 0.55 mmol) in 90% TFA (10 mL) was stirred at 50 ° C for 4 h. The reaction was monitored by LCMS. The mixture was treated with MeOH (5 mL)EtOAc. By the residue was purified by preparative HPLC to give compound 56 (46mg, 27%). ESI-MS: m/z 306.1 [M+H] ⁺ .

Example 47

Using the procedure described for the preparation of 52-4 from 52-3 , in the same manner from 57-1 (0.11 g; 0.18 mmol) and bis(isopropoxycarbonyloxymethyl)triethylammonium phosphate (0.35 mmol) Compound 57-2 (120 mg, 72%) was prepared from THF (2.5 mL) EtOAc (EtOAc)

The method of claim 55 for using the compound from acetonitrile containing 57-2 (25mg) of (0.1 mL) and 4N HCl / dioxane (8 uL) Preparation of Compound 57 (14mg, 77%). MS: m/z = 658 [M + 1].

Example 48

Compound 60

BSA (110 g, 541 mmol) was added to a stirred solution of EtOAc (EtOAc, EtOAc) The mixture was then cooled to room temperature and treated with 60-1 (55 g, 93.2 mmol) The mixture was refluxed overnight. After the starting material disappeared, the reaction was quenched with saturated NaHCO ₃ solution, and extracted with EA. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated to dryness. The residue was purified on a EtOAc EtOAc (EtOAc:EtOAc)

Treatment of compound 60-2 (35g, 0.06mol) containing NH MeOH (7N, 200mL) ₃ at the room temperature. The mixture was stirred at room temperature for 24 hours. The completion of the reaction was judged by LCMS. The mixture was concentrated under reduced pressure and the residue was purified elut elut elut elut elut eluting

To a solution of cyclopentanone (6 g, 8.33 mmol) and trimethoxymethane (8 mL) in MeOH (60 mL) EtOAc. The material was quenched with EtOAc (EtOAc:EtOAcEtOAcEtOAc The organic layer was dried over anhydrous Na ₂ SO _4, and concentrated to give 1,1-dimethoxy-low pressure cyclopentane. Add TsOH (2.1 g, to a solution of 60-3 (30 g, 0.11 mol) and 1,1-dimethoxycyclopentane (57 g, 0.44 mol) in 1,2-dichloroethane (200 mL). 0.011 mol) and the mixture was heated to 60 ° C overnight. The reaction was quenched with triethylamine and concentrated to dryness. The residue was washed with MeOH to afford 60-4 (30 g, 82%).

At room temperature to 60-4 (10g, 30mmol) in anhydrous CH of the ₃ CN (100mL) was added IBX (8.4g, 30mmol, 1.05 equiv.). The mixture was refluxed for 12 hours and then cooled to 0 °C. The precipitate was removed by filtration, and the filtrate was evaporated to ethylamine .

The crude product 60-5 (10 g, 30 mmol) was dissolved in EtOAc EtOAc . 37% HCHO (10 mL) and 2N aqueous NaOH (20 mL) were added at room temperature. The mixture was stirred overnight at room temperature and adjusted to pH = 7. At 0 ℃ mixture was treated with NaBH ₄ (4.44g, 120mmol). The reaction was stirred at room temperature for 30 minutes, followed by saturated aqueous NH ₄ Cl quenched. The mixture was extracted with EA. The organic layer was dried over Na ₂ SO _4, concentrated to dryness and a low pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

Tf ₂ O (8.5 g, 30.3 mmol) was added dropwise to a stirred solution of 60-6 (5.0 g, 13.8 mmol) and pyridine (5 mL) in DCM (20 mL). The solution was slowly warmed to 0 ° C, stirred at 0 ° C for 0.5 h and washed with EtOAc (0.5 M). The DCM layer was dried and concentrated to a low pressure, and the residue was purified on silica gel column obtained as 60-7 (4.5g, 52%) of a white solid.

TBAF (5.0 g, 19.2 mmol) was added to a solution of 60-7 (3.0 g, 4.8 mmol) in MeCN (10 mL). The reaction was allowed to proceed overnight. The reaction was monitored by HPLC and LCMS. An aqueous sodium hydroxide solution (about 1 equivalent of 1 N) was added, and the solution was stirred for 1 hour. The mixture was partitioned between a saturated solution of ammonium chloride and EA. The organic layer was separated and concentrated under reduced pressure. The crude product was purified on a EtOAc EtOAc EtOAc (EtOAc) ESI-MS: m / z 367.0 [M + H] +, 389.0 [M + Na] +.

Compound 60-8 (0.2 mmol) was dissolved in 80% HCOOH (10 mL). The solvent was evaporated and co-evaporated with a methanol/toluene mixture to remove traces of acid. The residue was dissolved in methanol containing 20% triethylamine for 15 min and evaporated. Compound 60 (65-68%) was isolated by silica gel chromatography (methanol gradient from 5% to 20% in DCM). MS: m/z 321.0 [M-1].

Example 49

A mixture of compound 45 (30 mg, 0.09 mmol), PTSA (18 mg, 1 eq.) and trimethyl orthoformate (0.3 mL; 30 eq.) in dioxane (1 mL) was stirred at room temperature for 1 day. With NH ₃ / MeOH and the reaction was followed by filtration. The filtrate was dissolved in a mixture of THF (0.5 mL) and 80% aqueous AcOH (0.25 mL). The solution was kept at room temperature for 1 hour and then evaporated. On silica gel (10g column with _{CH 2 Cl 2 / MeOH (4-15} % gradient)) obtained residue was purified 63-1 (30mg, 91%).

Using the method of preparing 52-4 from 52-3 , in the same manner from 63-1 (30 mg, 0.08 mmol) and bis(isopropoxycarbonyloxymethyl)triethylammonium phosphate (0.12 mmol) with DIPEA ( 56μL), BopCl (40mg) and 3-nitro-1,2,4-triazole (18 mg of) of THF (1mL) preparation of compound 63-2 (28mg, 52%). Using _{CH 2 Cl 2 / MeOH (4-10} % gradient).

Compound 63 (15 mg, 67%) was prepared from 63-2 (24 mg) using EtOAc . Using _{CH 2 Cl 2 / MeOH (4-10} % gradient). MS: m/z = 636 [M + 1].

Example 50

Compound 64-1 (8 mg, 40%) was prepared from compound 50 (17 mg) and trimethyl orthoformate (0.15 mL) and dioxane (0.5 mL) containing monohydrate PTSA (9 mg) in the same manner as 63-1 . ).

In the same manner as 63-2 , from 64-1 (8 mg, 0.02 mmol) and bis(isopropoxycarbonyloxymethyl)triethylammonium phosphate (0.036 mmol) and DIPEA (14 μL), Compound 64-2 (10 mg, 72%) was prepared from EtOAc (EtOAc:EtOAc)

Self-64-2 (24mg) Preparation of Compound 64 (15mg, 67%) in the same manner as the 63. MS: m/z = 652 [M + 1].

Example 51

Compound 65

Commercially available chloromethyl methyl carbonate (5.0 g) was treated with NaI to give 65a (5.38 g). The benzyl phosphate (silver salt) was reacted with 65a to give purified 65b (1.5 g) as described for compound 54 . ¹ H-NMR (CD ₃ CN): δ 7.39-7.42 (m, 5H), 5.60 (d, 4H), 5.11 (d, 2H), 3.8 (s, 6H). ³¹ P-NMR (CD ₃ CN): δ -4.47 ppm. Deprotection of compound 65b (415 mg; 1.7 mmol) afforded 65-1 (triethylamine salt) Reaction of compound 54-6 (320 mg; 0.9 mmol) with 65-1 (510 mg) gave purified 65-2 (400 mg). Compound 65-2 (230 mg) was deprotected to give purified compound 65 (250 mg). The foregoing reaction was carried out by the method described in the preparation of Compound 54 . ¹ H-NMR (CDCl ₃ ): δ 9.00 (s, 1H), 7.55 (d, 1H), 5.93 (s, 1H), 5.81 (d, 1H), 5.66 - 5.75 (m, 4H), 4.76 (dd , 2H), 4.37-4.46 (m, 2H), 4.15 (d, 2H), 3.86 (t, 6H), 3.70 (d, 6H), 1.65 (s, 6H), 1.25 (s, 3H). ³¹ P-NMR (CDCl ₃ ): δ -4.13 ppm.

Example 52

Compound 66a was prepared from 1,3-dimethoxypropan-2-ol. ¹ H-NMR (CDCl ₃ ) δ 5.73 (s, 2H), 5.03-5.06 (m, 1H), 3.59 (d, 4H), 3.38 (s, 6H). To the phenylmethyl phosphate (silver salt) (5 mmol) was added anhydrous ACN (25 mL), followed by 66a (3.12 g; 12 mmol). The suspension was heated at 60 ° C for 18 hours. After removal of the solid by filtration, EtOAc/EtOAc (3:1) was used to elute the product to afford 66b (540mg, 50%) as a colourless liquid. ¹ H-NMR (CD ₃ CN): δ 7.39-7.42 (m, 5H), 5.61 (d, 4H), 5.10 (d, 2H), 4.97-5.01 (m, 2H), 3.50-3.52 (m, 8H) ), 3.30 (s, 6H), 3.28 (s, 6H). ³¹ P-NMR (CD ₃ CN): δ -4.42 ppm. Compound 66b (540mg; 1.0mmol) removing the protecting group to obtain 66-1 (triethylammonium salt), which was used immediately without further purification. Compound 54-6 (285 mg; 0.8 mmol) was reacted with 66-1 to give purified 66-2 (300 mg). Compound 66-2 (300 mg) was deprotected to give purified compound 66 (290 mg). The foregoing reaction was carried out by the method described in the preparation of Compound 54 . ¹ H-NMR (CDCl ₃ ): δ 9.35 (s, 1H), 7.56 (d, 1H), 6.1 (s, 1H), 5.66-5.82 (m, 5H), 5.04 (s, 1H), 4.76 (dd , 2H), 4.60 (d, 1/2H), 4.37-4.48 (m, 2H), 4.22 (d, 2H), 4.06 (s, 1H), 3.58 (s, 8H), 3.57 (s, 12H), 1.93 (s, 1H), 1.23 (s, 3H). ³¹ P-NMR (CDCl ₃ ): δ -4.08 ppm.

Example 53

Using the method described for compound 44 , in the same manner from 54-6 (0.18 g, 0.5 mmol) and bis(ethyloxymethyl)phosphoric acid triethylammonium (1.0 mmol) with DIPEA (0.35 mL), BopCl (0.25 g) and 3-nitro-1,2,4-triazole (0.11 g) in THF (1 mL). Compound 67-1 (180 mg, 62%) using CH ₂ Cl ₂ /i-PrOH (4- Purification was carried out with a 10% gradient).

The method of claim 44 for the use of compounds from (85 mg of) Preparation of Compound 67 (60mg, 78%) 67-1 . MS: m/z = 1 027 [2M-1].

Example 54

Compound 68

BZCl (23.3 g, 165.5 mmol) was added to a solution of 68-1 (15 g, 50.2 mmol) in anhydrous pyridine (180 mL). The mixture was stirred overnight at room temperature. The mixture was diluted with EA, and washed with aqueous NaHCO _3. The organic layer was dried over anhydrous Na ₂ SO _4, and concentrated to dryness. The organic layer was dried and concentrated to obtain a residue, which by silica gel column chromatography (inclusive of PE 15% EtOAc) to afford a white solid of 68-2 (27g, 93.5%).

Compound 68-2 (27 g, 47 mmol) was dissolved in 90% HOAc (250 mL) and warmed to 110. The mixture was stirred at 110 ° C overnight. The solvent was removed and diluted with EA. The mixture was washed with aq. NaHCO ₃ and brine. The organic layer was dried and concentrated to give crude product 68-3 .

Compound 68-3 was dissolved in NH ₃ / MeOH (600mL) and stirred overnight. The solvent was concentrated to give EtOAc EtOAc m .

To a solution of 68-4 (15 g, 56.8 mmol) in dry EtOAc (200 mL), EtOAc (EtOAc, EtOAc, The mixture was stirred overnight. The solvent was removed and diluted with EA. The mixture was washed with aq. NaHCO ₃ and brine. The organic layer was dried and concentrated to obtain a crude product 68-5.

Trimethylpyridine (6.8 g, 56.8 mmol), MMTrCl (17.8 g, 56.8 mmol) and AgNO ₃ (9.6 g, 56.8 mmol) were added to a solution of 68-5 in anhydrous DCM (200 mL). . The mixture was stirred overnight. The mixture was filtered and the _aqueous filtrate was washed with brine and NaHCO. The organic layer was dried over Na ₂ SO _4, and concentrated to a low pressure to obtain a residue, which by silica gel column chromatography (inclusive of PE 5% EA) to afford 68-6 (32g, 87%).

Compound 68-6 (32 g, 49.2 mmol) was dissolved in a solution of TBAF in THF (1M, 4 eq.). The mixture was stirred overnight and the solvent was removed. The mixture was diluted with EA and washed with water. The organic layer was dried <RTI ID=0.0>: </RTI> to EtOAc ( EtOAc )

(, 38.8mmol 21g) (200mL) in DCM the solution was added pyridine 68-7 (9.2mL, 116.4mmol). The solution was cooled to 0 °C and Dess-Martin periodinane (49 g, 116.4 mmol) was added in one portion. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with Na ₂ S ₂ O ₃ solution and aqueous sodium bicarbonate. The mixture was stirred for 15 minutes. The organic layer was separated, washed with brine brine and evaporated. The residue was dissolved in dioxane (200 mL) andEtOAc was evaporated eluting The mixture was stirred at room temperature overnight and add NaBH ₄ (8.8g, 232.8mmol). After stirring at room temperature for 0.5 hour, excess aqueous sodium hydroxide solution was removed with ice water. The mixture was diluted with EA. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography eluting elut elut elut eluting

Compound 68-8 (4.8 g, 8.5 mmol) was co-evaporated twice with toluene. The residue was dissolved in anhydrous DCM (45 mL)EtOAcEtOAc The solution was cooled to 0 ° C and trifluoromethanesulfonic anhydride (4.8 g, 18.7 mmol) was added dropwise over 10 min. At this temperature, the reaction was stirred for 40 minutes. TLC (PE with 50% EA) showed completion of the reaction. The mixture was purified by column chromatography ( EtOAc EtOAc EtOAc EtOAc )

Compound 68-9 (6.1 g, 7.3 mmol) was dissolved in MeCN (25 mL). The mixture was treated with a solution of TBAF in THF (1M, 25 mL). The mixture was stirred overnight. THF (1 M, 15 mL) containing TBAF was added and stirred for 4 hours. The mixture was treated with aqueous sodium hydroxide (1 N, 14.6 mmol) and stirred for 1 hour. The reaction was quenched with water (50 mL) EtOAc. The organic layer was dried <RTI ID=0.0>: </RTI> to EtOAc ( EtOAc )

To a solution of 68-10 (1.5 g, 2.6 mmol) in dry EtOAc (15 mL) EtOAc. The mixture was stirred for 2 hours. The solvent was removed and diluted with EA. The mixture was washed with aq. NaHCO ₃ and brine. The organic layer was dried <RTI ID=0.0>: </RTI> EtOAc ( EtOAc )

At room temperature, to 68-11 (1.5g, 2.2mmol) in dry CH of the ₃ CN _(11mL) was added DMAP (671mg, 5.5mmol), TEA (555mg, 5.5mmol) and TPSCl (1.66g, 5.5 mmol). The reaction was stirred at room temperature overnight. NH ₄ OH (10 mL) was added, and the mixture was stirred for 2 hr. The mixture was diluted with EA and washed with NaHCO ₃ solution. The organic layer is concentrated in a dry and low pressure. By silica gel column chromatography (2% MeOH in the DCM) to obtain the crude product The residue was purified 68-12, which is obtained by purified by preparative TLC as a white solid of 68-12 (1.2g, 80%).

A solution of 68-12 (1.2 g, 1.76 mmol) in 80% HCOOH (60 mL) was stirred for 4 hr. Remove solvent at low pressure. The crude product was dissolved in MeOH (40 mL) and stirred overnight. The solvent was concentrated to obtain a crude product which by column chromatography on silica gel (DCM MeOH containing of 10%) to afford a white solid of compound 68 (480mg, 92%). ESI-MS: m/z 591 [2M+H] ⁺ .

Example 55

Tf ₂ O (3.27 g, 11.59 mmol) was added to a solution of 68-8 (2.63 g, 4.64 mmol) The mixture was stirred at room temperature for 40 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography by obtaining 69-1 (2.60g, 67%).

Sodium hydride (153 mg, 3.82 mmol) was added to a solution of 69-1 (2.65 g, 3.19 mmol. The solution was used in the next step without purification. The solution was treated with LiCl (402 mg, 9.57 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was dried over Na ₂ SO _4, and concentrated to a low pressure to obtain a crude product 69-2.

To a solution of 69-2 (1.81 g, 3. <RTI ID=0.0></RTI></RTI><RTIgt; The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography to afford 69-3 (l.

To a solution of 69-3 (925 mg, 1.58 mmol) in dichloromethane <RTI ID=0.0>(</RTI><RTIID=0.0></RTI></RTI><RTIgt; The mixture was diluted with EA (20 mL) and brine. The organic phase was concentrated under reduced pressure to give a crude material. The residue was purified by column chromatography to afford 69-4 (1.0 g, 90%).

Add TPSCl (1.34 g, 4.45 mmol), DMAP (543 mg, 4.45 mmol) and TEA (450 mg, 4.45 mmol) to a solution of 69-4 (1.24 g, 1.78 mmol) in dry EtOAc (10 mL) The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was crystallised from EA (30mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on silica gel to obtain a white solid of 69-5 (1.0g, 81%).

Compound 69-5 (1.0 g, 1.43 mmol) was treated with EtOAc ( EtOAc ) EtOAc . The solvent was removed under reduced pressure, and using 5% MeOH in CH ₂ Cl ₂ the residue was purified to give compound 69 (264mg, 60%) on silica gel. ESI-MS: m/z 311.9 [M+H] ⁺ .

Example 56

Benzyl phosphate (silver salt) and commercially available chloromethyl isobutyrate (5.0 g) yielded purified 70a (3.84 g). ¹ H-NMR (CD ₃ CN): δ 7.39-7.42 (m, 5H), 5.60 (d, 4H), 5.09 (d, 2H), 1.94-1.96 (m, 2H), 1.12-1.17 (m, 12H) ). ³¹ P-NMR (CD ₃ CN): δ -4.03 ppm. The compound 70a (780 mg; 2.0 mmol) was evaporated to give the title compound. Compound 54-6 (356 mg; 1.0 mmol) was reacted with 70-1 to give purified 70-2 (230 mg). Compound 70-2 (230 mg) was deprotected to give purified compound 70 (80 mg, 0.14 mmol). The foregoing reaction was carried out by the method described in the preparation of compounds 54 and 66 . ¹ H-NMR (CDCl ₃ ): δ 8.25 (s, 1H), 7.55 (d, 1H), 5.93 (s, 1H), 5.81 (d, 1H), 5.66 - 5.75 (m, 4H), 4.76 (dd , 2H), 4.37-4.46 (m, 2H), 4.15 (d, 2H), 3.86 (t, 6H), 3.70 (d, 6H), 1.65 (s, 6H), 1.25 (s, 3H). ³¹ P-NMR (CDCl ₃ ): δ -4.41 ppm.

Example 57

Compound 71-2 (0.34 g, 60%) was prepared from acetone (6 mL) containing 52-1 (0.33 g) and 71-1 (0.34 g) and NaI (0.19 g) and K ₂ CO ₃ (0.69 g).

In the same manner from 71-2 (0.25 g, 0.45 mmol) and bis(ethoxycarbonyloxymethyl)phosphoric acid triethylammonium (0.9 mmol) with DIPEA (0.35 mL), BopCl (0.25 g) and 3- Compound 71-3 (0.28 g, 74%) was prepared from THF (1. Purification was carried out using hexanes/EtOAc (30-100% gradient).

A solution of 71-3 (0.28 g, 0.33 mmol) in 80% aqueous AcOH was heated at 45 ° C for 4 h then concentrated. The residue with toluene, and then co-evaporated with MeOH containing a small amount of Et ₃ N (2 drops) of. Purification on silica gel (10 g column with CH ₂ Cl ₂ /i-PrOH (4-10% gradient)) afforded 71-4 (0.22 g, 84%).

To a solution of 71-4 (148 mg, 0.18 mmol) in EtOAc (EtOAc) (EtOAc)EtOAc. Diethyl ether was added and compound 71 was precipitated. The mixture was filtered and washed with diethyl ether to afford compound 71 (100 mg, 75%). The foregoing reaction was carried out by the method described in the preparation of Compound 52 . MS: m/z = 704 [M + 1].

Example 58

Compound 33-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated three times with dry toluene. To a solution of 33-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol). The mixture was stirred at 0 °C for 30 minutes, and TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 ° C for 30 minutes until a clear solution was observed. The mixture was heated to 70 ° C and stirred overnight. The solution was cooled to room temperature and diluted with EA (100 mL). The solution was washed with a saturated solution of NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc: EtOAc) ESI-MS: m/z 628 [M+H] ⁺ .

Under N _2, to 33-2 (48.0g, 76.4mol), AgNO 3 (50.0g, 294.1mmol) and collidine (40 mL) in dry DCM (200mL) in small parts of carve was added MMTrCl ( 46.0 g, 149.2 mmol). The mixture was stirred at room temperature under N ₂ for 3 hours. The completion of the reaction was judged by TLC. After filtration, the filtrate was washed with a saturated NaHCO ₃ solution and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc (EtOAc: EtOAc ESI-MS: m/z 900.1 [M+H] ⁺ .

Sodium (8.7 g, 378.0 mmol) was dissolved in anhydrous EtOH (100 mL) at EtOAc. Compound 33-3 (68.0 g, 75.6 mmol) was treated with a freshly prepared NaOEt solution and stirred at room temperature overnight. The completion of the reaction was judged by TLC and LCMS. A low pressure mixture was concentrated, diluted with H ₂ O (100mL), and extracted with EA (3 × 100mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ESI-MS: m/z 598 [M+H] ⁺ .

Compound 33-4 (32.0 g, 53.5 mmol) was co-evaporated 3 times with anhydrous pyridine. At 0 ℃ to 33-4 (32.0g, 53.5mmol) in dry pyridine (100 mL) in the ice cold solution was added dropwise TsCl (11.2g, 58.9mmol) in pyridine (50mL) in the. The mixture was stirred at 0 ° C for 18 hours. The reaction monitored by LCMS, and quenched with H ₂ O. A low-pressure solution was concentrated, and the residue was dissolved in EA (100mL), and washed with saturated NaHCO ₃ solution. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc ESI-MS: m/z 752 [M+H] ⁺ .

NaI (45.9 g, 306.0 mmol) and TBAI (2.0 g) were added to a solution of 33-5 (23.0 g, 30.6 mmol) in acetone (150 mL), and the mixture was refluxed overnight. The completion of the reaction was judged by LCMS. The mixture was concentrated at low pressure and the residue was dissolved in EA (100 mL). Solution was washed with brine, and dried over anhydrous Na ₂ SO _4. The organic solution was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjj DBU (14.0 g, 91.8 mmol) was added to aq. The reaction was monitored by LCMS. Reaction was quenched with a saturated solution of NaHCO _3, and extracted with EA (100mL) and extracted solution. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc EtOAc . ESI-MS: m/z 580 [M+H] ⁺ .

NIS (3.9 g, 17.2 mmol) and TEA ̇3HF (3.3 g, 20.7 mmol) were added to an ice-cold solution of 33-6 (8.0 g, 13.8 mmol) in anhydrous MeCN (100 mL). The mixture was stirred at room temperature for 18 hours and the reaction was checked by LCMS. After completion of the reaction, the reaction was quenched with a saturated Na ₂ SO ₃ solution and a saturated NaHCO ₃ solution. The solution was extracted with EA (3 x 100 mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc:EtOAc ESI-MS: m/z 726 [M+H] ⁺ .

To a solution of 33-7 (7.2 g, 9.9 mmol) in EtOAc (EtOAc)EtOAc. The mixture was stirred overnight and checked by LCMS. With saturated NaHCO ₃ solution. The mixture was washed. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc:EtOAc ESI-MS: m/z 934 [M+H] ⁺ .

To a solution of 33-8 (7.5 g, 8.0 mmol) EtOAc. The mixture was stirred at 90 ° C for 36 hours. The mixture was diluted with H ₂ O (100mL), and extracted with EA (3 × 150mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ESI-MS: m/z 928 [M+H] ⁺ .

Compound 33-9 (4.0g, 4.3mmol) and dry toluene coevaporated three times, and treated with _{NH 3 / MeOH (50mL, 4N} ) at room temperature. The mixture was stirred at room temperature for 18 hours. The completion of the reaction was judged by LCMS. The mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ESI-MS: m/z 616 [M+H] ⁺ .

Compound 33-10 (300.0 mg, 0.49 mmol) was co-evaporated three times with dry toluene and dissolved in MeCN (2 mL). The mixture was treated with NCN (120.5 mg, 1.47 mmol) and chlorophosphoric acid reagent (326.3 mg, 0.98 mmol) in MeCN (1 mL). The mixture was stirred at room temperature for 18 hours and was monitored by LCMS. The mixture was diluted with a 10% NaHCO3 solution and extracted with EtOAc (3.times.30mL). The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc : ESI-MS: m/z 913.0 [M+H] ⁺ .

Compound 33-11 (210 mg, 0.26 mmol) was taken eluted eluted elute The completion of the reaction was judged by LCMS. Mixture was concentrated under low pressure and by silica gel column chromatography (with the DCM MeOH, 1-3%) to afford compound was obtained as a solid of 33 (71.8mg, 48.7%). ESI-MS: m/z 641.3 [M+H] ⁺ .

Example 59

A mixed solution of 1-5 (317 mg, 0.49 mmol), TPSCl (373 mg, 1.23 mmol), DMAP (150 mg, 1.23 mmol) and TEA (124 mg, 1.23 mmol) in anhydrous MeCN was stirred overnight. The mixture was treated with an ammonium solution, followed by stirring at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography by obtaining 75-1 (200mg, 63%).

A solution of 75-1 (286 mg, 0.45 mmol) and ammonium fluoride (500 mg, 13.5 mmol) in methanol (10 mL) was refluxed overnight. The solvent was removed and the residue was purified on silica to give compound 75 (75mg, 57%) under reduced pressure. ESI-MS: m/z 289.9 [M+H] ⁺ .

Example 60

From 52-3 (0.88g, 1.48mmol) and bis(isobutylphosphonium oxymethyl)triethylammonium phosphate (3mmol) with DIPEA (1.05mL), BopCl (0.76g) and 3-nitro-1,2 Compound 76-1 (0.44 g, 34%) was obtained from 4-triazole (0.34 g) THF (10 mL). Purification was carried out using hexane/EtOAc (5-100% gradient). From 76-1 (0.44g) Preparation of compound 76-2 (0.43g, 85%); and self-contained 76-2 (0.22g) of EtOH (10mL) and 10% Pd / C (10mg) , 4N HCl / two dioxane (132 L) and the compound of preparation 76 (0.19g, 98%) under H ₂ atmosphere. The foregoing reaction was carried out by the method described in the preparation of Compound 52 . MS: m/z = 700 [M + 1].

Example 61

Compound 77

At 0 ℃, under N _2, to 77-1 (2.0g, 7.12mmol) was added TMSCl (3.86g, 35.58mmol) in pyridine (20mL) was stirred in the solution. The mixture was slowly warmed to room temperature and stirred for 2 hours. PivCl (1.71 g, 14.23 mmol) was added and the mixture was stirred for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in EA (50 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a low pressure to obtain a crude product. The crude product was dissolved in MeOH (20mL) was added and the _{NH 4 F (1.4g, 37.86mmol)} . The mixture was refluxed for 2 hours. The solvent was removed and the residue was purified mpjjjjjjjjj

To a solution of 77-2 (8.5 g, 23.28 mmol) and 1,1-dimethoxycyclopentane (2 mL) in a mixture of DMF (15 mL) and cyclopentanone (6 mL), TsOH (6.63 g, 34.93 mmol). The mixture was stirred at room temperature for 12 hours. The reaction was quenched with triethylamine and concentrated at low pressure. The residue was purified by column chromatography to afford 77-3 (6.5 g, 65%).

MeONa (2.25 g, 41.76 mmol) was added to a stirred solution of 77-3 (6.0 g, 13.92 mmol) EtOAc. The mixture was stirred for 12 hours and then neutralized with HOAc. The mixture was concentrated under reduced pressure and the residue was purified to purified crystalljjjjjjjj

At room temperature under N _2, to 77-4 (5.0g, 14.40mmol) in anhydrous pyridine of (50mL) was added TBSCl (3.24g, 21.61mmol) was stirred solution, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and the residue was purified to purified crystalljjjjjjj

At room temperature under N _2, to 77-5 (5.0g, 10.84mmol in anhydrous DCM (50mL) was added in the MMTrCl (5.01g, 16.26mmol) was stirred solution of trimethyl pyridine (5mL) and AgNO ₃ (2.76 g, 16.26 mmol), and the mixture was stirred for 2 hr. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to afford 77-6 (7.1 g, 89%).

At room temperature under N _2, to 77-6 (7.1g, 9.68mmol) in dry (70 mL) in the THF was added to a stirred solution of TBAF (5.05g, 19.37mmol), and the mixture was stirred for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to afford 77-7 (5.1 g, 87%).

At room temperature under N _2, was added DMP (3.28g, 7.75mmol are stirred solution of 77-7 (3.2g, 5.17mmol) and pyridine (2.04g, 25.85mmol) in dry DCM (30mL) was ). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with ₂ S ₂ O ₃ saturated solution, Na, and washed with saturated NaHCO ₃ solution and brine. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography to afford EtOAc (l. To the stirred solution of aldehyde (1.8 g, 2.92 mmol) in dioxane (29.2 mL) was added 37% EtOAc (EtOAc, EtOAc, The mixture was stirred at room temperature for 1.5 hours. Neutralize the solution with HOAc. (, 43.8mmol 1.66g) mixture was treated with EtOH (15mL) and NaBH _4, and stirred at room temperature for 2 hours. The mixture was quenched with water and concentrated at low pressure. The residue was purified by column chromatography to afford 77-8 (2.01 g, 61%).

At room temperature, under N _2, to 77-8 (200mg, 0.31mmol) was added TBDPSCl in the anhydrous (2mL) was stirred with DCM solution (170mg, 0.62mmol) and imidazole (42mg, 0.62mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM (10 mL) and brine. The organic phase was concentrated under reduced pressure and the residue was purified mjjjjjjj

At room temperature under N _2, was added BzCl (63mg, 0.61mmol), DMAP (74mg, 0.61mmol) and TEA in to the 77-9 (270mg, 0.304mmol) in dry DCM (2mL) stirred solution of (61 mg, 0.61 mmol). The mixture was stirred at room temperature until the starting material disappeared. The mixture was evaporated under reduced pressure, and the residue was purified by column chromatography to afford 77-10 (250mg, 83.3%).

The compound 77-10 (300 mg, 0.302 mmol) in THF (5 mL) was taken from EtOAc (EtOAc) The mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to afford 77-11 (170 mg, 75%).

At room temperature under N _2, was added Tf ₂ O (299mg, 1.06mmol) and pyridine (84mg, 1.06mmol) was stirred in to the 77-11 (400mg, 0.531mmol) in anhydrous DCM (4mL) solution via . The mixture was stirred at room temperature until the starting material disappeared. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to afford 77-12 ( 401mg , 85%).

At room temperature under N _2, of TBAF containing THF (1.0M, 2mL) treating compound 77-12 (500mg, 0.564mmol). The mixture was diluted with water (20 mL) and extracted with DCM. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAcjjjjjjj ESI-MS: m/z 652.1 [M+H] ⁺ .

Compound 77-13 (50 mg) was dissolved in 80% HCOOH (10 mL), and the mixture was warmed at 45 ° C for 24 hours. The solvent was evaporated and co-evaporated with methanol/toluene to remove traces of acid. The residue was dissolved in methanol containing 20% triethylamine for 15 min then evaporated. Compound 77 (18 mg, 75%) was isolated by silica gel chromatography eluting with EtOAc EtOAc. MS: m/z 312.5 [M-1].

Example 62

Compound 78a was prepared from commercially available 3-hydroxyoxetane (5.0 g). ¹ H-NMR (CDCl ₃ ) δ 5.73 (s, 2H), 5.48-5.51 (m, 1H), 4.90 (d, 2H), 4.72 (d, 2H). Compound 78b (8.0 g) was prepared from 78a . ¹ H-NMR (CDCl ₃ ) δ 5.95 (s, 2H), 5.48-5.51 (m, 1H), 4.90 (d, 2H), 4.72 (d, 2H). The benzyl phosphate (silver salt) was reacted with 78b (8.0 g) to give purified 78c (1.92 g). ¹ H-NMR (CD ₃ CN): δ 7.39-7.42 (m, 5H), 5.62 (d, 4H), 5.39-5.42 (m, 2H), 5.15 (d, 2H), 4.80-4.83 (m, 4H) ), 4.56-4.60 (m, 4H). ³¹ P-NMR (CD ₃ CN): δ -4.55 ppm. Deprotection of compound 78c afforded 78-1 (triethylammonium salt) which was used without further purification. Compound 54-6 (356 mg; 1.0 mmol) was reacted with 78-1 to afford purified 78-2 (230mg). Compound 78-2 (230 mg) was deprotected to give purified compound 78 (12.5 mg, 0.02 mmol). The foregoing reaction was carried out by the method described in the preparation of Compound 54 . ¹ H-NMR (CDCl ₃ ): δ 8.25 (s, 1H), 7.54 (d, 1H), 5.90 (s, 1H), 5.81 (d, 1H), 5.66-5.75 (m, 4H), 5.44-5.49 (m, 2H), 4.88-4.92 (m, 5H), 4.61- 4.78 (m, 5H), 4.37-4.46 (m, 2H), 4.21 (s, 1H), 3.49 (s, 1H), 1.25 (s) , 3H). ³¹ P-NMR (CDCl ₃ ): δ -4.28 ppm.

Example 63

From the compound 83-1 (90 mg; 0.1 mmol) and bis(isopropoxycarbonyloxymethyl)triethylammonium phosphate (0.2 mmol) and DIPEA (87 μL) as described for the preparation of compound 44 Compound 83-2 (70 mg, 58%) was obtained from EtOAc ( EtOAc m . Purification was carried out using a 20-80% gradient of hexanes / EtOAc.

Acetonitrile prepared as the compound 55, self-contained 83-2 (70mg) of (0.6 mL) and 4N HCl / dioxane (50 L) Preparation of Compound 83 (25mg, 64%). MS: m/z = 658 [M + 1].

Example 64

Compound 84

As described in the preparation of compound 44 , from 84-1 (52 mg; 0.08 mmol) and bis(isopropoxycarbonyloxymethyl)triethylammonium phosphate (0.16 mmol) and DIPEA (74 μL), BopCl (51 mg) Compound 84-2 (69 mg, 90%) was obtained from THF (1 mL). Purification was carried out using a 20-100% gradient of hexanes / EtOAc.

Compound 44 prepared as described, from 84-2 (65mg) Preparation of Compound 84 (27mg, 62%). MS: m/z = 626 [M + 1].

Example 65

The mixture was stirred and 76-2 of acetic anhydride in pyridine at room temperature overnight, and then concentrated on silica gel (10g column with _{CH 2 Cl 2 / i-PrOH} (4-10% gradient)) to obtain the purified 85- 1 (12 mg, 69%).

Under H ₂ atmosphere in the same manner as Compound 52, self-contained 85-1 (12mg) of EtOH (0.5mL) and 10% Pd / C (1mg) , Preparation of Compound 4N HCl / dioxane (7μL) 85 (10 mg, 92%). MS: m/z = 742 [M + 1].

Example 66

Freshly prepared anhydrous EtOH containing EtONa (2N, 150 mL) was added to a solution of 20-4 (13.67 g, 17.15 mmol) in EtOH (50 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc

At room temperature, the PPh ₃ (2.73g, 10.4mol) in anhydrous pyridine (60 mL) was added in a solution of I ₂ (2.48g, 9.76mmol), and the reaction mixture was stirred at room temperature for 30 minutes. A solution of 86-1 (3.9 g, 6.51 mmol) in pyridine (10 mL) was obtained. The mixture was stirred overnight at room temperature. , Followed by extraction with EA (100 mL) with Na ₂ S ₂ O ₃ saturated aqueous NaHCO ₃ solution and the reaction was quenched. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified with EtOAc EtOAc EtOAc ( EtOAc:EtOAc

To 86-2 in the anhydrous THF (300mL) was added DBU (14.0g, 91.8mmol), and the mixture was heated to reflux for 3 hours. Concentrate the mixture at low pressure. The residue was dissolved in EA (100 mL) and brine. Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc ( EtOAc )

NIS (0.975 g, 4.3 mmol) and TEA ̇3HF (0.82 g, 5.16 mmol) were added to an ice-cold solution of 86-3 (2.0 g, 3.44 mmol) in anhydrous MeCN (20 mL). The mixture was stirred at room temperature for 2 hours. With saturated Na ₂ SO ₃ and the reaction was quenched with aqueous NaHCO ₃ was then concentrated under a low pressure. The residue was dissolved in EA (50mL), washed with brine, dried over anhydrous Na ₂ SO _4, and the low pressure evaporator. The residue was purified by EtOAc EtOAc ( EtOAc )

To a solution of 86-4 (1 g, 1.37 mmol) in EtOAc (EtOAc) The reaction was stirred for 30 min and checked by LCMS. The mixture was concentrated under reduced pressure and the residue was dissolved in EA (50 mL). The solution was washed with brine. The organic layer was dried over MgSO _4, and the low pressure evaporator. The residue was purified by EtOAc EtOAc ( EtOAc )

Add NaOBz (3.46g, 24mmol) and 15-crown--5 (4.5mL) in a solution of the 86-5 (2g, 2.4mmol) in dry DMF (40mL). The mixture was stirred at 95 ° C for 72 hours. The mixture was then diluted with EA (100 mL) and washed with water and brine. The organic phase was dried over MgSO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

It was stirred at room temperature containing compound 86-6 (1.35g, 1.64mmol) of NH ₃ / MeOH (150mL) for 18 hours. The mixture was concentrated at mp EtOAc ( EtOAc ) ESI-MS: m/z 618.3 [M+H] ⁺ .

Triethylamine (92.7 μL, 0.64 mmol) was added to a solution of 86-7 (99 mg, 0.16 mmol). The mixture was cooled to 0 to 5 ° C (ice/water bath), and freshly prepared and distilled isopropyl dichlorophosphate (36.6 μL, 0.2 mmol, according to the procedure Reddy et al. J. Org. Chem. 2011 ) was added to the mixture . , 76(10) , 3782-3790)). The mixture was stirred at 0 to 5 ° C (ice/water bath) for 15 minutes, then N-methylimidazole (26.3 μL, 0.32 mmol) was added. The mixture was then stirred at 0 to 5 ° C for 1 hour. TLC showed no 86-7 present. EA (100 mL) was added followed by water. The organic layer was washed with a saturated aqueous solution of H ₂ O, NH ₄ Cl and brine. The organic layer was separated, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was silica gel (with zero to 10% iPrOH / DCM) to obtain the purified 86-a and 86-b of a mixture of (61.5mg).

The mixture of 86-a and 86-b of (61.5mg, 0.085mmol) was dissolved in anhydrous CH ₃ CN (0.5mL), and was added 4N HCl containing of dioxane at 0 to 5 ℃ (ice / water bath) ( 64 μL). The mixture was stirred at room temperature for 40 minutes and anhydrous EtOH (200 μL) was added. The solvent was evaporated at room temperature and co-evaporated 3 times with toluene. The residue was dissolved in _{50% CH 3 CN / H 2} O and purified using acetonitrile and water on a reverse phase HPLC (C18), followed by lyophilization to obtain Compound 86 (1.8mg) and compound 87 (14.5mg).

Compound 86 : ¹ H NMR (CD ₃ OD-d ₄ , 400 MHz) δ 8.0 (s, 1H), 6.69 (d, J = 16.0 Hz, 1H), 5.9-5.6 (br s, 1H), 4.94 - 4.85 ( m,1H), 4.68-4.52 (m, 3H), 1.49-1.3 (m, 12H); ¹⁹ F NMR (CD ₃ OD-d ₄ ) δ -122.8 (s), -160.06 (s); ³¹ P NMR (CD ₃ OD-d ₄ ) δ -7.97 (s). ESI-LCMS: m / z = 450.1 [M + H] +; Compound _{^{87: 1 H NMR (CD 3}} OD-d 4, 400MHz) δ 7.96 (s, 1H), 6.68 (s, 1H), 6.69 (d , J = 16.8 Hz, 1H), 6.28-6.1 (br s, 1H), 4.81 - 4.5 (m, 4H), 1.45-1.39 (m, 12H); ³¹ P NMR (CD ₃ OD-d ₄ ) δ - 5.84(s). ESI-LCMS: m/z = 450 [M+H] ⁺ .

Example 67

Compounds 88 and 89

Triethylamine (141 μL, 2.0 mmol) was added to a solution of 88-1 (150 mg, 0.24 mmol). The mixture was cooled to 0 to 5 ° C (ice/water bath) and freshly prepared and distilled isopropyl dichlorophosphate (45 μL, 0.26 mmol, according to the procedure Reddy et al. J. Org. Chem. 2011 , 76 (10) ) , 3782-3790 preparation). The mixture was stirred at 0 to 5 ° C (ice/water bath) for 15 minutes, then N-methylimidazole (40 μL, 0.49 mmol) was added. The mixture was stirred at 0 to 5 ° C for 1 hour. TLC showed the absence of starting material 88-1 . EA (100 mL) was added followed by water. The organic layer was washed with a saturated aqueous solution of H ₂ O, NH ₄ Cl and brine. The organic layer was separated, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified on EtOAc (EtOAc: EtOAc : EtOAc: EtOAc: Structure).

Compounds 88-2a and 88-2b were deprotected using the procedures described herein. To give compound 88 (7.3mg, individual isomers 88-2a from the (16.5mg, 0.0235mmol)) and the compound 89 (29.0mg, 88-2b from the individual isomers (72.7mg, 0.1mmol)).

Compound 88 : ¹ H NMR (CD ₃ OD-d ₄ , 400 MHz) δ 7.94 (s, 1H), 6.32 (s, 1H), 6.00-5.9 (br s, 1H), 4.9-4.487 (m, 1H), 4.83-4.77 (m, 1H), 4.65-4.50 (m, 3H), 1.45-1.39 (s, 9H), 1.2 (s, 3H); ¹⁹ F NMR (CD ₃ OD-d ₄ ) δ -120.3 (s ³¹ P NMR (CD ₃ OD-d ₄ ) δ -5.19 (s); ESI-LCMS: m/z=448.05 [M+H] ⁺ . Compound 89 : ¹ H NMR (CD ₃ OD-d ₄ , 400 MHz) δ 7.98 (s, 1H), 6.34 (s, 1H), 5.78-5.64 (br s, 1H), 4.95-4.48 (m, 2H), 4.62-4.52 (m, 3H), 1.48-1.42 (s, 9H), 1.1 (s, 3H); ¹⁹ F NMR (CD ₃ OD-d ₄ ) δ -121.3 (s); ³¹ P NMR (CD ₃ OD -d ₄ ) δ -7.38 (s); ESI-LCMS: m/z = 448.05 [M+H] ⁺ .

Example 68

At 0 to 5 ℃ to 90-1 (532mg, 1.84mmol) in dry was added N- methylimidazole (2.0mL, 24.36mmol) in of CH ₃ CN (8.0mL) stirred solution, followed by addition of freshly prepared and Distilled isopropyl dichlorophosphate solution (0.5 mL, 2.84 mmol). The solution was stirred at room temperature for 15 hours. The mixture was diluted with EA and water (15 mL). The solution was washed with H ₂ O, 50% aqueous citric acid and brine. The organic layer was separated, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to give a crystal crystal crystal crystal crystal crystal crystal crystal The crude product was re-purified using acetonitrile and water on reverse phase HPLC (C18), then lyophilized to afford compound 90 (43.6mg). MS: m/z = 395.05 [M+H] ⁺ , 393.0 [MH] ^- , 787.05.0 [2M-H] ^- .

Example 69

Anhydrous 51 (0.05 mmol) was dissolved in a mixture of PO (OMe) ₃ (0.7 mL) and pyridine (0.3 mL). The mixture was evaporated under vacuum at a bath temperature of 42 ° C for 15 minutes and then cooled to room temperature. Was added N- methylimidazole (0.009mL, 0.11mmol), followed by POCl ₃ (9μL, 0.11mmol), and the mixture was kept at room temperature for 20-40 minutes. The reaction was controlled by LCMS and monitored by the appearance of 96 . Separation was performed by RP HPLC on a Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of 0 to 30% methanol in 50 mM triethylammonium acetate buffer (pH 7.5) was used to dissolve. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess buffer to give compound 96 . MS: m/z 369.0 [M-1].

Example 70

Anhydrous 51 (0.05 mmol) was dissolved in a mixture of PO (OMe) ₃ (0.7 mL) and pyridine (0.3 mL). The mixture was evaporated under vacuum at a bath temperature of 42 ° C for 15 minutes and then cooled to room temperature. Was added N- methylimidazole (0.009mL, 0.11mmol), followed by PSCl ₃ (9μL, 0.11mmol), and the mixture was kept at room temperature for 20-40 minutes. The reaction was controlled by LCMS and monitored by the appearance of the nucleoside 5'-phosphorothioate. After completion of the reaction, tetrabutylammonium pyrophosphate (150 mg) and DMF (0.5 mL) were sequentially added to obtain a homogeneous solution. After 1.5 hours at ambient temperature, the reaction was quenched with water (10 mL). The 5'-triphosphate was isolated as a mixture of diastereomers by IE chromatography on a AKTA Explorer using a column of HiLoad 16/10 with high efficiency Q agarose. The separation was carried out in a linear gradient of 0 to 1 N NaCl in 50 mM TRIS buffer (pH 7.5). The fractions containing the thiotriphosphate were combined, concentrated, and desalted by RP HPLC on a Synergy 4 micron Hydro-RP column (Phenominex). The dissolution was carried out using a linear gradient of 0 to 30% methanol in 50 mM triethylammonium buffer at a flow rate of 10 ml per minute over 20 minutes. Compounds 97 and 98 were collected. Analytical RP HPLC was performed on a Synergy 4 micron Hydro-RP column (Phenominex) in a linear gradient of 0 mM to 25% acetonitrile in 50 mM triethylammonium acetate buffer, pH 7.5, over 7 minutes. Compound 97 : RT 5.50 min. ³¹ P NMR: δ +42.45 (1P, d), - 6.80 (1P, d), -23.36 (1P, q). MS: m/z 544.9 [M-1]. Compound 98 : RT 6.01 min. ³¹ P NMR: δ +41.80 (1P, d), - 6.57 (1P, d), -23.45 (1P, q). MS: m/z 544.9 [M-1].

Example 71

10% Pd/C (30 mg) was added to a solution of 99a (0.31 g, 0.8 mmol) in anhydrous methanol (2 mL), and the mixture was stirred for 1 hour under H ₂ atmosphere. After completion, the mixture was filtered and the catalyst cake was washed with methanol. The washings and filtrate were combined. The solvent was removed in vacuo to afford EtOAc (EtOAc: EtOAc) ¹ H NMR (CDCl ₃ , 400 MHz) δ 5.57 (d, J =13.6 Hz, 4H), 4.23 (q, J = 7.2 Hz, 4H), 1.30 (t, J = 7.2 Hz, 6H), ³¹ P NMR ( CDCl ₃ ) δ -4.64 (s).

Add 99-1 (160 mg, 0.45 mmol), diisopropylethylamine to a solution of bis(EOC) triethylammonium phosphate (0.7 mmol, prepared from 213 mg of 99b and 0.2 mL of TEA) in THF (3 mL) (0.33 mL, 1.8 mmol), BOP-Cl (229 mg, 0.9 mmol) and 3-nitro-1,2,4-triazole (103 mg, 0.9 mmol). The mixture was stirred at room temperature for 90 minutes. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give a white solid, which was silica gel column _{(CH 3 OH: DCM; 9.5} : 0.5) to obtain 99-2 (189mg, 66%) was purified on.

A solution of 99-2 (180 mg, 0.28 mmol) in 80% HCOOH (7 mL) was warm. The solvent was evaporated and then co-evaporated 3 times with toluene. Use containing from 0 to 10% DCM MeOH the residue was purified on a silica gel column, is obtained after lyophilization as a white foam of compound 99 (97.3mg). MS: m/z = 575.1 [M + H] ⁺ .

Example 72

Compound 100a was prepared from commercially available 2-(2-methoxyethoxy)-ethanol (11.56 mL). Compound 100a (13.5 g) was obtained as a clear, colorless oil. ¹ H-NMR (CDCl ₃ ) δ 5.73 (s, 2H), 4.38-4.40 (m, 2H), 3.74-3.77 (m, 2H), 3.64-3.67 (m, 2H), 3.54-3.57 (m, 2H) ), 3.39 (s, 3H). Compound 100b (9.6 g) was prepared from 100a and a slightly colored clear oil was obtained. ¹ H-NMR (CDCl ₃ ) δ 5.96 (s, 2H), 4.38-4.40 (m, 2H), 3.74-3.77 (m, 2H), 3.64-3.67 (m, 2H), 3.54-3.57 (m, 2H) ), 3.39 (s, 3H). Benzyl phosphate (silver salt) was reacted with 100b (2.4 g) and purified 100c (1.02 g) was obtained. ¹ H-NMR (CD ₃ CN): δ 7.39-7.42 (m, 5H), 5.60 (d, 4H), 5.11 (d, 2H), 4.27-4.29 (m, 4H), 3.65-3.67 (m, 4H) ), 3.56 (t, 4H), 3.46 (t, 4H), 3.30 (s, 6H). ³¹ P-NMR (CD ₃ CN): δ -4.55 ppm. The compound 100c (620 mg; 1.15 mmol) was taken-up to give the title compound ( 100% ). Compound 54-6 (356 mg; 1.0 mmol) was reacted with 100-1 to give purified 100-2 (250 mg). The compound 100-2 (250 mg) was deprotected to give purified compound 100 (110 mg, 0.14 mmol). The foregoing reaction was carried out by the method described in the preparation of Compound 54 . ¹ H-NMR (CDCl ₃ ): δ 8.62 (s, 1H), 7.54 (d, 1H), 5.96 (s, 1H), 5.64 - 5.79 (m, 5H), 4.76 (dd, 2H), 4.37-4.46 (m, 6H), 4.25 (d, 2H), 3.86 (s, 1H), 3.75 (t, 4H), 3.70 (t, 4H), 3.58 (t, 4H), 3.38 (s, 6H), 1.65 ( s, 6H), 1.25 (s, 3H). ³¹ P-NMR (CDCl ₃ ): δ -3.90 ppm.

Example 73

Compound 44 (0.010 g, 0.016 mmol) was added to a standard physiological brine solution (3 mL, pH 7.3) and stored in a hot block at 37 ° C for 6 days. By preparative HPLC, a Synergi 4u Hydro-RP column (Phenomenex, 00G-4375-U0-AX) was used, using H ₂ O (0.1% formic acid) and ACN (0.1% formic acid) solvent (0-65% in 20 minutes). The mixture was purified by gradient. The compound was dissolved at 13.0 minutes. Concentration and lyophilization of the pure fractions gave Compound 104 (0.005 g, 63%). MS: m/z = 487 [M + 1].

Example 74

A mixture of 102-1 (45 mg, 0.06 mmol) and butylamine (0.4 mL) was kept at room temperature overnight and then evaporated. On silica gel (10g column with _{CH 2 Cl 2 / MeOH (4-12} % gradient)) to obtain crude residue was purified on a colorless glass of 102-2 (20mg, 56%).

To a solution of 102-2 (20 mg, 0.03 mmol) in ACN (0.5 mL). The mixture was stirred at rt for 4 h then quenched with MeOH. The residue was treated with ACN to obtain an off-white solid of compound 102 (9mg, 80%). MS m/z = 328 [M + 1].

Example 75

To a solution of 105-1 (50 g, 203 mmol) in EtOAc (EtOAc) The reaction was carried out overnight at room temperature. The residue was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was separated, washed with EtOAc EtOAc EtOAc EtOAc

Silver nitrate (66.03 g, 388.4 mmol) and trimethylpyridine (235 mL, 1.94 mol) were added to a solution of 5'- OTBDPS ether (94.0 g, 194.2 mmol) in anhydrous DCM (300 mL). The mixture was stirred at room temperature. After 15 minutes, the mixture was cooled to 0 ° C and monomethoxytrityl chloride (239.3 g, 776.8 mmol) was added as a separate portion. After stirring at room temperature overnight, the mixture was filtered over celite, and filtrate was diluted with EtOAc. The solution was washed sequentially with 1 M citric acid, dilute brine and 5% sodium bicarbonate. Drying organic solution by sodium sulfate The liquid was concentrated in vacuo to give a complete protected intermediate in the form of a yellow foam.

The fully protected intermediate was dissolved in toluene (100 mL) and the solution was concentrated under reduced pressure. The residue was dissolved in dry EtOAc (250 mL)EtOAcEtOAc The mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with saturated sodium bicarbonate then brine. After drying over MgSO4, EtOAc (EtOAc m.)

Of pyridine are added (13.5g, 26mmol) in DCM (100mL) in a solution of 105-2 (6.17mL, 78mmol). The solution was cooled to 0 ° C and Dess-Martin periodinane (33.8 g, 78 mmol) was added as a separate portion. The reaction mixture was stirred at room temperature for 4 hours and was quenched by addition of Na ₂ S ₂ O ₃ solution (4%) and aqueous sodium hydrogen carbonate (4%) (the solution was adjusted to pH 6, about 150 mL). The mixture was stirred for 15 minutes. The organic layer was separated, washed with brine brine and evaporated. The residue was dissolved in dioxane (100 mL). EtOAc (EtOAc) The reaction mixture was stirred at room temperature overnight. After stirring at room temperature for 0.5 hours to remove excess aqueous sodium hydroxide saturated with NH ₄ Cl (about 150mL). The mixture was concentrated under reduced pressure and the residue was partitioned betweenEtOAc and EtOAc The organic phase was separated, washed with brine, dried over magnesium sulfate By column chromatography (2% MeOH in the DCM) is obtained residue was purified white foam of 105-3 (9.2g, 83.6%).

Compound 105-3 (23 g, 42.0 mmol) was co-evaporated twice with toluene. The residue was dissolved in anhydrous DCM (250 mL) EtOAc. The solution was cooled to 0 ° C and trifluoromethanesulfonic anhydride (24.9 g, 88.1 mmol) was added dropwise over 10 min. At this temperature, the reaction was stirred for 40 minutes. The reaction was monitored by TLC (PE: EA = 2:1 and DCM:MeOH = 15:1). After completion, the reaction mixture was quenched with water (50 mL). The mixture was stirred for 30 minutes and extracted with EA. The organic phase was dried over Na ₂ SO ₄ and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure. EtOAc m .

NaH (260 mg, 6.5 mmol) was added to a stirred solution of 105-4 (4.4 g, 5.42 mmol) in anhydrous DMF (50 mL). The solution was stirred at room temperature for 1.5 hours. The solution was used in the next step without any further treatment.

NaN ₃ (1.5 g, 21.68 mmol) was added to the stirred solution under a nitrogen atmosphere at 0 ° C, and the obtained solution was stirred at room temperature for 1.5 hr. The reaction was quenched with water, extracted with EA, washed with brine and dehydrated over MgSO _4. The concentrated organic phase was used in the next step without further purification.

NaOH (5.4 mL, 2 M in water) was added to a solution of 105-6 (3.0 g, 5.4 mmol) in anhydrous 1,4-dioxane (18 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction was diluted with EA, washed with brine, and dehydrated over MgSO _4. The concentrated organic phase was purified on a silica gel column (30% EtOAc) to afford white crystals :

Compound 105-7 (520 mg, 0.90 mmol) was dissolved in 80% HCOOH (20 mL). The mixture was stirred for 3 hours and monitored by TLC. The solvent was removed and the residue was taken 3 times with MeOH &EtOAc. NH ₃ /MeOH was added and the reaction mixture was stirred at room temperature for 5 min. The solvent was concentrated to dryness and the residue was purified by column chromatography by was obtained as a white solid of compound 105 (120mg, 44.4%). ESI-LCMS: m / z 302.0 [M + H] +, 324.0 [M + Na] +.

Example 76

Compound 106

At 25 ℃, under N ₂ atmosphere, was added MMTrCl (1.77g, 5.76mmol) was stirred in to 105-7 of (1.1g, 2.88mmol) in dry DCM (10mL) over a solution, AgNO ₃ (1.47g, 8.64 mmol) and trimethylpyridine (1.05 g, 8.64 mmol). The reaction was refluxed for 12 hours. MeOH (20 mL) was added and the solvent was removed to dry. The residue was purified on a silica gel column (20% EtOAc) to afford 10-1 (1.6 g, 85.1%) as a white foam.

TPSCl (570 mg, 1.89 mmol), DMAP (230 mg, 1.89 mmol) and TEA (190 mg, 1.89 mmol) were added to a stirred solution of 106-1 (800 mg, 0.947 mmol) in anhydrous MeCN (10 mL). ). The mixture was stirred for 12 hours. NH ₄ OH (25 mL) was added, and the mixture was stirred for 2 hr. The solvent was removed and the yellow foam residue was purified on a silica gel column. Further purification by preparative TLC gave 106-2 (700 mg, 87.1%).

Compound 106-2 (300 mg, 0.355 mmol) was dissolved in 80% HCOOH (5 mL). The mixture was stirred for 3 hours and monitored by TLC. The solvent was then removed and the residue was taken (3) with MeOH &EtOAc. NH ₃ /MeOH was added and the mixture was stirred at room temperature for 5 min. The solvent was removed and the residue was purified by column chromatography by was obtained as a white solid of compound 106 (124mg, 82.6%). ESI-LCMS: m / z 301.0 [M + H] +, 601.0 [2M + H] +.

Example 77

Compound 108

To a stirred suspension of 108-1 (20 g, 77.5 mmol), PPh ₃ (30 g, 114.5 mmol), imidazole (10 g, 147 mmol) and pyridine (90 mL) in anhydrous THF (300 mL) was added dropwise I (25g, 98.4mmol) in THF (100 mL) of ₂ in. The mixture was allowed to warm to room temperature and stirred at room temperature for 10 hours. The reaction was quenched by MeOH (100 mL). The solvent was removed and the residue was dissolved in a mixture of ethyl acetate (EA) and THF (2L, 10:1). The organic phase was washed with Na ₂ S ₂ O ₃ saturated solution, and a mixture of THF with EA (2L, 10: 1) extraction of the aqueous phase. The organic layer was combined and concentrated to give a crystallite crystal crystal crystal crystal crystal crystal crystal crystal crystal ¹ H NMR: (DMSO- d ₆ , 400 MHz) δ 11.42 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 5.82 (s, 1H), 5.63 (d, J = 8.0 Hz, 1H) , 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79 (m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H).

At room temperature, under N _2, to 108-2 (24.3g, 66.03mmol) in dry the added NaOMe in MeOH (240mL) stirred solution of (10.69g, 198.09mmol). The mixture was refluxed for 3 hours. The solvent was removed and the residue was redissolved in anhydrous pyridine (200 mL). Ac ₂ O (84.9 g, 833.3 mmol) was added to the mixture at 0 °C. The mixture was warmed to 60 ° C and stirred for 10 hours. The solvent was removed, and the residue was diluted with DCM, washed with sat NaHCO ₃ and brine. The organic layer was concentrated and purified on a EtOAc EtOAc EtOAc ( EtOAc:EtOAc ¹ H NMR: (CDCl ₃ , 400 MHz) δ 8.82 (s, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.54 (s, 1H), 5.85 (s, 1H), 5.77 (dd, J = 8.0,2.0Hz, 1H), 4.69 (d , J = 2.4Hz, 1H), 4.58 (d, J = 2.8Hz, 1H), 2.07 (d, J = 5.2Hz, 6H), 1.45 (s, 3H) .

To an ice-cold solution of 108-3 (15 g, 46.29 mmol. I ₂ (23.51 g, 92.58 mmol) of anhydrous DCM (1.0 L) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 5 hours. , And extracted with DCM with a saturated Na ₂ S ₂ O ₃ and the reaction was quenched with NaHCO _3. The organic layer was separated, dried and evaporated to dryness. The residue was purified on EtOAc EtOAc ( EtOAc:EtOAc : ¹ H NMR: (methanol-d _4, 400 MHz) δ 7.52 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.73 (d, J = 8.0 Hz, 1H), 3.58 (s, 1H), 3.54 (d, J = 6.8 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.58 (s, 3H).

To a solution of 108-4 (7.0 g, 14.89 mmol) in dry EtOAc (400 mL), Na.sub.2 (21.44 g, 14. The reaction mixture was stirred at 130 ° C for 6 hours. The solvent was removed, diluted with EA and washed with water and brine. The organic layer was evaporated and purified on a silica gel column (PE containing 10-30% EA) to afford 108-5 (2.8 g, 40.5%). ESI-MS: m/z 444.9 [M-F+H] ⁺ .

A mixture of 108-5 (4.0 g; 8.6 mmol) and liquid ammonia was kept overnight in a high pressure stainless steel vessel at room temperature. Then ammonia was evaporated, and the Silica (50g column, having a _{2 2} / MeOH solvent mixture CH Cl (4-12% gradient)) and the residue was purified compound was obtained as a colorless foam of 108 (2.0g; 84% yield rate). ESI-MS: m/z 275.1 [MH] ^- .

Example 78

Compounds 109 and 110

Anhydrous compound 108 (14mg, 0.05mmol) was dissolved in a mixture of PO (OMe) ₃ (0.750mL) and pyridine (0.5mL) in the. The mixture was evaporated under vacuum at a bath temperature of 42 ° C for 15 minutes and then cooled to room temperature. N-methylimidazole (0.009 mL, 0.11 mmol) and POCl ₃ (0.009 mL, 0.1 mmol) were added sequentially. The mixture was kept at room temperature for 45 minutes. Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutylammonium pyrophosphate (100 mg) were added. Anhydrous DMF (about 1 mL) was added to obtain a homogeneous solution. The reaction was quenched with 2 M aqueous ammonium acetate (1 mL, pH = 7.5) over 1 hour, diluted with water (10 mL) and loaded onto a column of HiLoad 16/10 with high-purity Q agarose. The separation was carried out in a linear gradient of 0 to 1 N NaCl in 50 mM TRIS buffer (pH 7.5). Fractions containing compound 109 parts of 60% buffer B and contains the compound 110 at 80% Buffer B fractions. The corresponding fractions were concentrated and the residue was purified by RP HPLC on EtOAc EtOAc EtOAc. A linear gradient of 0 to 30% methanol in 50 mM triethylammonium acetate buffer (pH 7.5) was used to dissolve. The corresponding fractions were combined, concentrated, and lyophilized 3 times to remove excess buffer. Compound 109 : P ³¹ -NMR (D ₂ 0): -3.76 (s); MS: 378.2 [M-1]. Compound 110 : P ³¹ -NMR (D ₂ 0): -9.28 (d, 1H, P?), -12.31 (d, 1H, P?), -22.95 (t, 1H, P?); MS 515.0 [M-1] .

Example 79

Compound 112

Compound 112 (36 mg, 63%) was synthesized using a neopentyl chlorophosphate reagent as described for compound 2. MS: 572.6 [M-1].

Example 80

Anhydrous compound 108 (14mg, 0.05mmol) was dissolved in a mixture of PO (OMe) ₃ (0.750mL) and pyridine (0.5mL) in the. The mixture was evaporated under vacuum at a bath temperature of 42 ° C for 15 minutes and then cooled to room temperature. Sequentially added N- methylimidazole (0.009mL, 0.11mmol) and PSCl ₃ (0.01mL, 0.1mmol). The mixture was kept at room temperature for 1 hour. Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutylammonium pyrophosphate (200 mg) were added. Anhydrous DMF (about 1 mL) was added to obtain a homogeneous solution. The reaction was quenched with 2 M aqueous ammonium acetate (1 mL, pH = 7.5) over 2 h, diluted with water (10 mL) and loaded onto a column of HiLoad 16/10 with high-purity Q agarose. The separation was carried out in a linear gradient of 0 to 1 N NaCl in 50 mM TRIS buffer (pH 7.5). The dissolved fraction was dissolved at 80% buffer B containing compounds 116 and 117 . The corresponding fractions were concentrated and the residue was purified by RP HPLC on EtOAc EtOAc EtOAc. A linear gradient of 0 to 20% methanol in 50 mM triethylammonium acetate buffer (pH 7.5) was used to dissolve. Collect two peaks. The corresponding fractions were combined, concentrated, and lyophilized 3 times to remove excess buffer. 1st peak (stronger polarity): ³¹ P-NMR (D ₂ O): +42.68 (d, 1H, Pα), -9.05 (d, 1H, Pγ), -22.95 (t, 1H, Pβ); MS 530.9.0 [M-1]. The second peak (weak polarity): ³¹ P-NMR (D ₂ O): +42.78 (d, 1H, Pα), -10.12 (bs, 1H, Pγ), -23.94 (t, 1H, Pβ); MS 530.9.0 [M-1].

Example 81

By RP-HPLC separation of Compound 5 non diastereomers. By on Synergi Hydro RP 30 × 250m 4u particle column (Phenomenex PN 00G-4375-U0 -AX) 26 minutes in H ₂ O gradient of 10-43% ACN eluting compound 121 (29.5 min) and compound 118 (30.1 minutes ). Lyophilization of the pure fractions gave a white powder. Compound 121 : ³¹ P-NMR (DMSO-d6): 3.448 ppm; MS: m/z: 544M-1; Compound 118 : ³¹ P-NMR (DMSO-d6) 3.538 ppm; MS: m/z: 544M-1.

Example 82

The diastereomer of compound 8 was isolated by RP-HPLC. By on Synergi Hydro RP 30 × 250m 4u particle column (Phenomenex PN 00G-4375-U0 -AX) 26 minutes in H ₂ O gradient of 25-52% ACN eluting compound 119 (24.8 min) and compound 120 (25.3 minutes ). Lyophilization of the pure fractions gave a white powder. Compound ^{119: 31 P-NMR (DMSO} -d6) 3.492ppm; MS: m / z: 584M-1. Compound 120 : ³¹ P-NMR (DMSO-d6): s.

Example 83

Compound 122-1 was synthesized using a procedure similar to the preparation of compound 2 using propyl propyl propyl ester hydrochloride. LCMS: m / z 592 [M -1] -.

To a solution of 122-1 (1.1 g, 1.85 mmol) in dioxane (15 mL) and water (3 mL). 100mg). The mixture was hydrogenated (balloon) for 2 hours and monitored by HPLC. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was suspended in a 3% solution (25 mL) of lithium perchloric acid in acetone. The solid was isolated by filtration, washed with acetone and dried in vacuo to afford compound 122 (yield: LCMS: m / z 426 [M -1] -.

Example 84

Compound 108 (40 mg, 0.14 mmol) and bis(p-pentyloxymethyl)triethylammonium phosphate (0.21 mmol, from 80 mg of bis(p-pentyloxymethyl) phosphate and by co-evaporation with pyridine and toluene in sequence 30 μL Et ₃ N) anhydrous. The evaporated residue was dissolved in dry EtOAc (2 mL)EtOAc Diisopropylethylamine (73 μL, 3 equivalents), BopCl (71 mg, 2 eq.) and 3-nitro-1,2,4-triazole (32 mg, 2 eq.) were added. The mixture was stirred at 0 ° C for 90 minutes. The mixture was then diluted with EtOAc, washed with saturated aqueous NaHCO ₃ and brine and dried (Na ₂ SO _4). Compound 151 (13 mg, 16%) was obtained on a silica gel column (with CH ₂ Cl ₂ /i-PrOH (4-10% gradient)) followed by RP-HPLC (A: water, B:MeCN). MS: m/z = 1167 [2M-1].

Example 85

To bis(isopropoxycarbonyloxyethyl-1)triethylammonium phosphate (0.28 mmol, prepared from 100 mg of bis(isopropoxycarbonyloxyethyl-1)phosphate and 40 μL of Et ₃ N) in THF To the solution was added 157-1 (60 mg, 0.18 mmol). The mixture was evaporated and made anhydrous by co-evaporation with pyridine and toluene. The evaporated residue was dissolved in anhydrous THF (2.5 mL) and evaporated. Diisopropylethylamine (94 μL, 3 equivalents), BOP-Cl (92 mg, 2 equivalents) and 3-nitro-1,2,4-triazole (41 mg, 2 equivalents) were added sequentially. The mixture was stirred at 0 ℃ 90 min, diluted with EtOAc and washed with saturated aqueous NaHCO ₃ and brine, and dried (Na ₂ SO _4). In the silica gel column (with _{CH 2 Cl 2 / i-PrOH} (3-10% gradient)) obtained residue was purified 159-2 (19mg, 17%).

A solution of 159-2 (19 mg, 0.03 mmol) in 80% aqueous HCOOH was stirred at room temperature for 90 min then concentrated. The residue with toluene, and then co-evaporated with MeOH containing a small amount of Et ₃ N (1 drop) of. In the silica gel column (with _{CH 2 Cl 2 / MeOH (4-10} % gradient)) to afford the compound 159 (5mg, 26%). MS: m/z = 629 [M-1].

Example 86

Compound 160

A mixture of benzyloxycarbonyl-L-proline (55 mg, 0.22 mmol) in THF (1 mL) and CDI (36 mg, 0.22 mmol) was stirred at room temperature for 1.5 hr then stirred at 40 ° C for 20 min. The solution was added to a mixture of compound 44 (122 mg, 0.2 mmol) and D.sub.3 (3 mg, 0.03 mmol) in DMF (1.5 mL) and TEA (0.75 mL). The mixture was stirred at 80 ° C for 1 hour. After cooling, the mixture was concentrated and the residue was partitioned between &lt The organic layer was washed with 0.1N citric acid, washed with saturated aqueous NaHCO ₃ and brine, and dried (Na ₂ SO _4). The residue was purified on a silica gel column eluting with CH ₂ Cl ₂ /i-PrOH (4-10% gradient) to afford 160-1 (83 mg, 50%) as colorless foam.

To a solution of 160-1 (83 mg, 0.1 mmol) in EtOH was added HCl (4N in dioxane; 50 μL, 2 eq.) and 10% Pd/C (5 mg). The mixture was stirred for 1 hour under a H ₂ atmosphere (normal pressure). The catalyst was removed by filtration through a pad of celite, and the filtrate was evaporated to afford compound 160 (50 mg) as a white solid. MS: m/z = 702 [M + 1].

Example 87

Compound 5-2 (32 mg, 0.1 mmol) was dissolved in dry THF (3 mL) and EtOAc (EtOAc) The reaction was kept at room temperature for 1 hour, and (isopropyl-L-alanine) phenyl chlorochlorophosphate (0.3 mmol) was added. The mixture was kept at room temperature overnight. LSMS analysis showed that approximately 20% of the starting material was unreacted. The same amount of Grignard reagent and thiochlorophosphate were added, and the mixture was heated at 37 ° C for 4 hours. With NH ₄ Cl The reaction was quenched. The product was extracted with EA, washed with brine, dried over Na ₂ SO ₄ and evaporated. The resulting oil was dissolved in 80% EtOAc (4 mL) and evaporated. Compound 113 was purified by RP HPLC on a Synergy 4u Hydro-RP column (Phenominex) with a gradient of 30% to 95% of methanol in water to afford a colourless solid. Compound 113 (7 mg, yield 12.5%). MS: m/z = 560.0 [MH].

Example 88

Compound 125-1 (109 mg) was dissolved in 80% HCOOH (15 mL) and kept at room temperature for 3 hr then evaporated. The residue was treated with NH ₃ / MeOH at room temperature for 1 hour to remove the by-products containing the methyl acyl. After evaporation, Compound 125 (52 mg, 86%) was obtained by purifying compound 125 using crystals of methanol. MS: 339.6 [M-1], 679.7 [2M-1].

Example 89

Compound 148-1 (15.0 g, 25.55 mmol) was treated with 90% HOAc (150 mL). The mixture was stirred at 110 ° C for 12 hours and then concentrated under reduced pressure. The residue was dissolved in DCM and the solution was washed with brine. The organic phase was dried over anhydrous Na ₂ SO _4, then concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

Processing 148-2 (12.0g, 24.79mmol) compound containing NH MeOH (200mL, 7M) ₃ at the room temperature. The solution was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

Stirring at 148-3 (4.3 g, 15.58 mmol), PPh ₃ (8.16 g, 31.15 mmol), imidazole (2.11 g, 31.15 mmol) and pyridine (15 mL) in dry THF (45 mL) the suspension was added dropwise I ₂ (7.91g, 31.15mmol) solution (100 mL) in the in THF. The mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was quenched with MeOH (100 mL). The solvent was removed at low pressure and the residue was redissolved in a mixture of EA and THF (0.2L, 10:1). The organic phase was washed with a saturated aqueous solution of Na ₂ S ₂ O ₃ (2×). The aqueous phase was extracted with a mixture of EA and THF (0.2 L, 10:1, 2×). Dried over anhydrous Na ₂ SO ₄ the combined organic phase concentrated. The residue was purified with EtOAc EtOAc EtOAc .

At room temperature under N _2, Compound 148-4 (800mg, 2.07mmol) was dissolved in a mixture of DBU (4mL) and THF (4mL) of the. The solution was stirred at room temperature for 1 hour. The mixture was neutralized with HOAc and extracted with a mixture of EA and THF (10:1, 40mL). The organic phase was washed with brine, and dried over anhydrous Na ₂ SO _4. The concentrated organic phase was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

Under N _2, to 148-5 (1.20g, 4.65mmol) in anhydrous MeCN was added NIS (1.57g, 6.97mmol) and TEA˙3HF (1.12g, 6.97mmol) (12mL ) in the ice cold solution. The mixture was stirred at room temperature for 5 hours. Reaction was quenched with a saturated solution of NaHCO _3, and extracted with EA (3 × 100mL). The organic phase was dried over anhydrous Na ₂ SO _4, evaporated to dryness and a low pressure. The residue was purified on a EtOAc EtOAc EtOAc EtOAc .

BzCl (0.83 g, 5.94 mmol), TEA (0.6 g, 5.94 mmol), and DMAP were continuously added to a stirred solution of 148-6 (1.2 g, 2.97 mmol) in anhydrous DCM (12 mL). 0.72 g, 5.94 mmol). The mixture was stirred at room temperature for 12 hours. The reaction was quenched with water and extracted with EtOAc EtOAc. The organic phase is concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

Tetrabutylammonium hydroxide (25.78 mL, 51.78 mmol) was neutralized to pH = 4 with TFA (4.3 mL), and the solution was added to a solution of 148-7 (1.09 g, 2.14 mmol) in DCM (30 mL) in. m-CPBA (1.85 g, 10.74 mmol) was added portionwise with vigorous stirring, and the mixture was stirred for 12 hr. The mixture was diluted with EA (100 mL) and brine. The organic phase is concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc :

Containing NH MeOH ₃ at the room temperature (10mL, 7M) treating compound 148-8 (280mg, 0.704mmol). The mixture was stirred at room temperature for 2 hours. Concentrate the mixture at low pressure. By column chromatography (0-10% MeOH containing of DCM) was obtained residue was purified as a white solid of compound 148 (110mg, 53.1%). ESI-LCMS: m/z 295.1 [M+H] ⁺ .

Example 90

Compound 150

To 150-1 (10g, 42mmol) in anhydrous MeCN was added (200mL) in a ice cold solution of TEA˙3HF (10g, 62.5mmol) and NIS (28g, 126mmol). The mixture was stirred at room temperature for 1.5 hours and was monitored by LCMS. After the reaction was completed, the mixture was concentrated at a low pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

To a solution of 150-2 (22 g, 57 mmol) EtOAc (EtOAc,EtOAc. The mixture was stirred at room temperature for 5 hours and monitored by LCMS. Solution, extracted with EA and washed with saturated NaHCO ₃ solution and brine. The organic phase was dried and filtered over anhydrous Na ₂ SO _4. Concentrate the filtrate at low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

To a solution of 150-3 (6.5 g, 11 mmol) EtOAc. The mixture was stirred at 95 ° C for 48 hours. The precipitate was removed by filtration and the organic solvent was removed at low pressure. The residue was dissolved in EA (200mL), and washed with a saturated solution of NaHCO ₃ solution and brine. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. Concentrate the filtrate at low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

(120mL, 7M) treating Compound 150-4 (3g, crude) containing the NH MeOH _3. The mixture was stirred for 3 hours and monitored by TLC. The solution was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc . ¹ H-NMR (CD ₃ OD, 400 MHz) δ =1.19 (s, 3H), 3.76-3.82 (m, 2H), 4.02 (d, J = 19.8 Hz, 1H), 5.70 (d, J = 8.07 Hz, 1H), 6.27 (s, 1H), 7.89 (d, J = 8.07 Hz, 1H).

Compound 150-5 (100 mg, 0.36 mmol) was co-evaporated three times with toluene. Add 150-C (255.6 mg, 0.72 mmol) to a stirred solution of 150-5 (100 mg, 0.36 mmol) in MeCN (1.0 mL) and NMI (295 mg, 3.6 mmol). A solution in MeCN (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with water and diluted with EtOAc EtOAc. The organic layer was washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ . The organic phase is concentrated under low pressure. The residue was purified on a silica gel column (yield 5% i- PrOH) to afford crude. By preparative HPLC (water containing 0.1% HCOOH and MeCN) was purified product obtained as a white solid of compound 150 (46.7mg, 23.3%). ESI-LCMS: m/z 618 [M+Na] ⁺ .

To a stirring solution of 150-A (2.0 g, 13.16 mmol) and naphthalen-1-ol (1.89 g, 13.16 mmol) in anhydrous DCM (100 mL) 13.16 mmol) in DCM (20 mL). After the addition, the mixture was gradually warmed to room temperature and stirred for 2 h. The solution was cooled to -78 ° C, and DCM (20 mL) containing EtOAc (2.20 g, 13.16 mmol). 26.29 mmol) of DCM (20 mL). The mixture was gradually warmed to room temperature and stirred for 2 hours. Remove organic solvents at low pressure. The residue was dissolved in methyl butyl ether. The precipitate was filtered and the filtrate was concentrated under reduced pressure. Purification on silica gel column (dry DCM) to obtain the residue as a colorless oil of 150-C (1.0g, 24.8% ).

Example 91

152-C (736 mg, 2.17 mmol, prepared as described below) was added dropwise to a solution of 150-5 (300 mg, 1.08 mmol) and NMI (892 mg, 10 mmol) in anhydrous MeCN (4 mL) A solution of anhydrous MeCN (1 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with water and diluted with EtOAc EtOAc. The organic layer was washed with water and brine. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. By silica gel column (DCM iPrOH containing of 1% to 5%) to obtain the crude residue was purified compound 152 (276mg, crude). By preparative HPLC (water containing 0.1% HCOOH and the MeCN) purification of the crude compound 152 (96 mg) was obtained as a pure white solid of compound 152 (46mg, 47.9%). ESI-LCMS: m/z 560 [MF] ⁺ .

To a solution of the compound 152 (180 mg, 0.31 mmol) in EtOAc (EtOAc) The mixture was stirred overnight at room temperature. The solution was quenched with water and concentrated at low pressure. The residue was dissolved in EA (10 mL) and brine. Na ₂ SO ₄ organic layers were dried over anhydrous. The organic phase is concentrated under low pressure. By silica gel column (DCM i-PrOH of containing, 1-3%) to afford a crude residue was obtained compound 153 (172mg). By preparative HPLC (water containing 0.1% HCOOH and the MeCN) purification of the crude Compound 153 was obtained as a pure white solid of compound 153 (46mg, 23.8%). ESI-LCMS: m/z 602.3 [MF] ⁺ .

150-C was prepared using the analogous procedure, using the 150-A (2.00g, 13.16mmol) and 4-chlorophenol (1.68g, 13.16mmol) Preparation of compound 152-C (1.02g, 23% , colorless oil) .

Example 92

Add TSOH to a solution of 165-1 (5 g, 0.02 mol), cyclopentanone (5.25 g, 0.06 mol, 4.5 eq.) and trimethoxymethane (6.52 g, 0.06 mol, 3 eq.) in MeCN (80 mL) ̇H ₂ O (1.95 g, 0.01 mol). The mixture was heated at 80 ° C overnight. Concentrate the mixture at low pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc :

IBX ( 5.33 g, 0.019 mol, 1.11 eq.) was added to a solution of 165-2 (5 g, 0.16 mol) in MeCN (50 mL, anhydrous). The mixture was heated at 80 ° C for 5 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give 165-3 (4.5 g, purity: 90%).

To a solution of 1 65-3 (5 g, 0.016 mol) and CH ₂ O (3.6 mL) in 1,4-dioxane (50 mL) was added EtOAc (11.3 mL, 2N). The mixture was stirred at room temperature for 5 hours. NaBH ₄ (1.48 g, 0.038 mol) was added at 0 ° C and stirred for 1 hour. The reaction was quenched with H ₂ O (30mL) and extracted with EA (3 × 30mL). The organic layer was washed by brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc

Tf ₂ O (3.27 mL, 0.019 mol) was added to a stirred solution of 165-4 (3 g, EtOAc). The mixture was slowly warmed to 0 ° C and stirred at 0 ° C for 2 hours. Washed with saturated NaHCO ₃ solution and extracted with DCM (3 × 30mL) with the mixture, and. The organic layer was separated and washed by brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc

NaH (0.977 g, 0.024 mol) was added to a solution of 165-5 (12.3 g, 0.02 mol) in DMF (20 mL). The mixture was stirred at room temperature for 3 hours. The mixture was treated with LiCl (2.6 g, 0.062 mol), followed by stirring for 2 hr. With H ₂ O (20mL) The reaction was quenched and extracted with EA (3 × 30mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc .

To a solution of 165-6 (12 g, 0.035 mol) in THF (120 mL), NaOH solution (38.8 mL, 0.038 mol) was added at 0 ° C and stirred at room temperature for 3 hours. The mixture was adjusted to pH = 7 using HCl (1.0N) solution and extracted with EA (3.times. The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

165-7 (3 g, 8.0 mmol) was co-evaporated with toluene (30 mL). Bz ₂ O (2.01 g, 1 eq.) was added to a solution of 165-7 (3 g), EtOAc ( EtOAc ). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with H ₂ O, and extracted with DCM (3 × 30mL). The DCM layer was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc

(, 0.43mmol 200mg) in the in CH ₃ CN (2mL, anhydrous) was added to 165-8 TPSCl (260mg, 2 eq), TEA (0.13mL) and DMAP (106.4mg, 2 eq). The mixture was stirred at room temperature for 2 hours.

The mixture was treated with NH ₃ ̇H ₂ O (33%, 1.33 mL) and stirred at room temperature for 2 hr. The reaction was quenched with EtOAc (EtOAc)EtOAc. The DCM layer was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAcjjjjjj

165-9 (100 mg, 0.216 mmol) was treated with HCOOH (7 mL, 80%) and stirred at room temperature for 3 hr. Concentrate the mixture at low pressure. The residue was purified by EtOAc EtOAc EtOAc .

At -60 ℃ containing the NH MeOH ₃ (10 mL) treated 165-10 (270mg, 0.68mmol). The mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 6 hours. Concentrate the mixture at low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

Example 93

To a solution of 106 (200 mg, 0.67 mmol) in dry EtOAc (5 mL) The mixture was stirred overnight and the reaction mixture was diluted with EA. The mixture was washed with aq. NaHCO ₃ and brine. The organic layer was dried, filtered and concentrated to obtain a residue, which was by silica gel column chromatography (5% MeOH in DCM to a solution of the 25% MeOH in DCM) to obtain a white solid of 169-1 (153mg, 55% ).

At room temperature, (54mg, 0.13mmol) in of anhydrous DCM (2mL) was added to 169-1 trimethyl pyridine (95μL, 0.78mmol), DMTrCl ( 262mg, 0.78mmol) and AgNO ₃ (66mg, 0.39 mmol). The mixture was stirred overnight then diluted with DCM (5 mL). Through diatomaceous earth filter funnel prefilled mixture, and washed with aqueous NaHCO _3, 1.0M citric acid solution followed by brine filtrate. The organic layer was dried over Na ₂ SO _4, and concentrated to a low pressure to obtain a residue. By silica gel column chromatography (inclusive of PE 25% EA to 100% EA) obtained residue was purified 169-2 (83.5mg, 63.6%).

To a solution of 169-2 (83 mg, 0.081 mmol) in EtOAc (1 mL) The mixture was stirred for 1.5 hours. The mixture was diluted with EA and washed with water and brine. The organic layer was dried <RTI ID=0.0></RTI> to EtOAc (EtOAc: EtOAc:

169-3 (66.6 mg, 0.074 mmol) was co-evaporated with toluene and THF (3×). Bis(POC) phosphate (33 mg, 0.96 mmol) was added followed by co-evaporation with toluene (3x). The mixture was dissolved in dry THF (1.5 mL) and cooled in ice (0 to 5 °C). 3-Nitro-1,2,4-triazole (13 mg, 0.11 mmol), diisopropylethylamine (54 μL, 0.3 mmol) and BOP-Cl (28 mg, 0.11 mmol) were continuously added. It was stirred at 0 to 5 ℃ mixture for 2 hours, diluted with EtOAc, washed with 1.0M citric acid, NaHCO ₃ saturated solution and brine, and dried over Na ₂ SO _4. In Silica (10g column with _{CH 2 Cl 2: i-PrOH} (4-10% gradient)) to obtain the residue was purified as a white solid of 169-4 (68mg, 76%) a.

169-4 (68 mg, 0.07 mmol) was dissolved in 80% HCOOH. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). The residue was dissolved in _{50% CH 3 CN / H 2} O in, ₃ CN and H ₂ O CH purification on reverse phase HPLC (C18). The lyophilized product gave 169 (4.8 mg, 14%) as a white foam. ESI-LCMS: m/z = 613.1 [M+H] ⁺ , 1225.2 [2M+H] ⁺ .

Example 94

AA-1 (2.20 g, 3.84 mmol) was dissolved in 80% HCOOH (40 mL) at room temperature (18 °C). The mixture was stirred at room temperature for 12 hours. Remove solvent at low pressure. By column chromatography using 50% EA containing the residue was purified hexane to obtain a white solid of AA-2 (1.05g, 91.3% ).

At room temperature (16 ℃), under N ₂ atmosphere, (, 3.32mmol 1g) in dry pyridine (20mL) in the stirred solution was added TBSCl to AA-2 (747mg, 4.98mmol) and imidazole (451mg, 6.64 mmol). The mixture was stirred at room temperature for 4 hours. The resulting solution was concentrated to dryness <RTI ID=0.0> , And dried over anhydrous MgSO ₄ solution and with a _saturated brine solution NaHCO. The solution was concentrated to dryness, and purified using 20% EA in hexane of the residue was obtained containing a white solid of the AA-3 (1.4g, 79.5% ) on a silica gel column.

At room temperature (15 deg.] C), the AA-3 (1.50g, 2.83mmol, 1.00 equiv) was added to dry the TPSCl in CH ₃ CN (28mL) stirred solution of (1.71g, 5.80mmol, 2.05 equiv.), DMAP (691.70 mg, 5.66 mmol, 2.00 eq.) and TEA (573.00 mg, 5.66 mmol, 2.00 eq.). The mixture was stirred for 2 hours. NH ₃ .H ₂ O (20 mL) was added, and the mixture was stirred for 3 hr. The mixture was extracted with EA (3 x 60 mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (30% EtOAc) to afford AA-4 (2.3 g, crude) as a yellow foam.

At room temperature (15 deg.] C), under N ₂ atmosphere, was added to a stirred DMTrCl in the AA-4 (1.90g, 2.34mmol) in dry DCM (20mL) over a solution of (1.82g, 3.49mmol) and 2, 4,6-trimethylpyridine (1.00 g, 8.25 mmol). The mixture was stirred at room temperature for 12 hours. MeOH (20 mL) was added. The mixture was filtered and the filtrate was concentrated to dry. The residue was dissolved in EA (80 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. On silica gel column (5% MeOH in the DCM) is obtained residue was purified as a white solid of the AA-5 (1.4g, crude).

AA-5 (2.40 g, 2.60 mmol) was dissolved in TBAF (10 mL, 1 M in THF). The mixture was stirred at room temperature (15 ° C) for 30 minutes. The mixture was concentrated to dryness and the residue was crystallised from EA The solution was washed with brine, dried MgSO ₄ On silica gel column (5% MeOH in the DCM) is obtained residue was purified as a white solid of AA (1.50g, 95.8%). ESI-MS: m/z 625.3 [M+Na] ⁺ .

At room temperature (15 deg.] C), under N ₂ atmosphere, to AA (60.0mg, 99.57μmol, 1.00 equiv) in pyridine (1 mL) was added in the isobutyric anhydride (31.50mg, 199.13μmol 1 part, 2.00 equivalents). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated and the residue was partitioned between EA and water. The organic layer was washed with water and the brine, and dried over anhydrous Na ₂ SO _4. The mixture was filtered and the filtrate was concentrated to dry. By silica gel chromatography (30% EA of containing PE) Purification of the residue obtained as a white solid of 145-1 (59.00mg, 79.77%).

The 145-1 (57.00mg, 76.74μmol, 1.00 equiv) was dissolved in _{80% CH 3 COOH (8mL)} . The solution was stirred at room temperature (15 ° C) for 12 hours. The mixture was concentrated to dryness. In the silica gel column (2.5% MeOH in DCM containing it) on the residue obtained was purified as a white foam of 145 (23.00mg, 68.05%). ESI-MS: m / z 441.2 [M + H] +, 463.2 [M + Na] +.

Example 95

145-1 similarities with the embodiment containing AA (60.00mg, 99.57μmol, 1.00 equiv) of pyridine (1 mL) and propionic anhydride (25.92mg, 199.13μmol, 2.00 equiv) Preparation 170-1. 170-1 (white solid, 56.00 mg, 78.69%).

170 was prepared in a similar manner to 145 using 170-1 (54.00 mg, 75.55 μmol, 1.00 eq.). 170 (white foam, 18.00 mg, 57.78%). ESI-MS: m/z 413.1 [M+H] ⁺ .

Example 96

In the manner similar to 145-1, containing AA (62.00mg, 102.89μmol, 1.00 equiv) of pyridine (1 mL) and valeric anhydride (38.32mg, 205.77μmol, 2.00 equiv) Preparation 171-1. 171-1 (white solid, 60.00 mg, 75.65%).

In a similar manner to 145 , 171 was prepared using 171-1 (75.00 mg, 97.30 μmol, 1.00 eq.). 171 (white foam, 28.00 mg, 61.43%). ESI-MS: m/z 469.2 [M+H] ⁺ .

Example 97

In the same manner as 169-4 , from 146-1 (50 mg, 0.087 mmol) and bis(isopropoxycarbonyloxymethyl)phosphate (58 mg, 0.175 mmol) and DIPEA (75 μL, 0.52) Preparation of 146-2 ( 40.7 mg, 53%) of THF (0.4 mL), EtOAc ( EtOAc ) .

The 146-2 (40mg, 0.045mmol) was dissolved in ₃ CN (0.5mL) in dry CH, and was added in dioxane (34μL, 0.135mmol) 4N HCl at 0 to the 5 ℃. The mixture was stirred at room temperature for 3 hours. Anhydrous EtOH (200 μL) was added. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). In Silica (10g column, with a gradient of 5-7% _{MeOH / CH 2 Cl 2 ()} ) and the residue was purified lyophilized to obtain a white foam of 146 (15.4mg, 76%). ESI-LCMS: m/z = 614.15 [M+H] ⁺ , 1227.2 [2M+H] ⁺ .

Example 98

172-1 (100 mg, 0.174 mmol) was co-evaporated with anhydrous pyridine (3×), toluene (3×) and CH ₃ CN (3×) and dried overnight under high vacuum. The 172-1 was dissolved in CH ₃ CN (2mL). Proton sponge (112 mg, 0.52 mmol), POCl ₃ (49 μL, 0.52 mmol) was added at 0 to 5 °C. The mixture was stirred at 0 to 5 ° C for 3 hours to obtain Intermediate 172-2 . To this solution was added L-propyl isopropylamine hydrochloride (146 mg, 0.87 mmol) and TEA (114 μL, 1.74 mmol). The mixture was stirred at 0 to 5 ° C for 4 hours. The mixture was stirred at 0 to 5 °C for 2 hours then diluted with EtOAc. Mixture was washed with 1.0M citric acid, washed with saturated aqueous NaHCO ₃ and brine, and dried over Na ₂ SO _4. On Silica (10g column with _{CH 2 Cl 2 / MeOH (0-7} % gradient)) to obtain the residue was purified as a white solid of 172-3 (67mg, 43.7%).

The 172-3 (65mg, 0.074mmol) was dissolved in ₃ CN (0.5mL) in dry CH, and was added in dioxane (55μL, 0.22mmol) 4N HCl at 0 to the 5 ℃. The mixture was stirred at room temperature for 1.5 hours. A second portion of 4N HCl in dioxane (15 μl) was added and the mixture was stirred at room temperature for 2 hr. Anhydrous EtOH (300 μL) was added. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). The residue was dissolved in _{50% CH 3 CN / H 2} O and purified on reverse phase HPLC (C18, with CH ₃ CN and water), and lyophilized to obtain a white foam of 172 (9mg, 20%). ESI-LCMS: m / z = 608.15 [M + H] +, 1215.3 [2M + H] +.

Example 99

Compound 173

At -75 ° C, 173-1 (4.7 g, 11.2 mmol; according to the procedure Villard et al., Bioorg. Med. Chem. (2008) 16: 7231-7329) and Et ₃ N (3.4 mL, 24.2 mmol) ) in THF (25mL) over 1 hour in the solution added dropwise to N, N - diisopropyl-dichloro (1.0mL, 5.5mmol) was stirred in a solution of () in the warp 35mL THF. The mixture was stirred at room temperature for 4 hours. The mixture was filtered and the filtrate was concentrated. The oily residue was purified on a silica gel column (EtOAc/hexane (2-20% gradient)) to afford 173 .

Was added 5- (ethylthio) tetrazole of ₃ CN (1.0mL) To a solution of 173-2 (50mg, 0.08mmol) and 173-3 (110mg, 0.11mmol) in CH (0.75mL, 0.16mmol; CH ₃ CN 0.25M). The mixture was stirred at room temperature for 1 hour. The mixture was cooled to -40 ℃, and 3-chloroperbenzoic acid was added a solution of _{2 Cl 2 (0.3mL) (37mg} , 0.16mmol) in CH. The mixture was allowed to warm to room temperature over 1 hour. The reaction was quenched with a solution of 7% Na ₂ S ₂ O ₃ in NaHCO ₃ sat. The mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with brine, and dried over Na ₂ SO _4. The solvent was evaporated, and the residue was purified mjjjjjjjjjjj

A solution of 173-4 (52 mg, 0.036 mmol) in MeCN (0.5 mL) and EtOAc (45 &lt The reaction was quenched with MeOH and solvent was evaporated. The residue was co-evaporated with toluene and the silica gel column (with a 4-10% gradient of _{MeOH / CH 2 Cl 2 ()} ) obtained was purified on a 173 (14mg, 51%). ESI-LCMS: m/z = 702 [M+H] ⁺ .

Example 100

A mixture of 174-1 (0.14 g, 0.24 mmol; according to the procedure described in WO 2008/082601, filed on December 28, 2007) and 173-2 (120 mg, 0.2 mmol) was dried over with pyridine, It was then dissolved in pyridine (3 mL). Pentylene chloride (48 μl) was added dropwise at -15 °C. The mixture was stirred at -15 ° C for 2 hours. The reaction was quenched with saturated aqueous NH ₄ Cl, and _diluted with ₂ Cl CH. The organic layer was washed with brine, and dried over Na ₂ SO _4. The solvent was evaporated and the residue was purified mjjjjjjjjj

Was stirred at rt 174-2 (43mg; 0.04mmol) in CCl ₄ (0.8mL), L- valine isopropyl ester hydrochloride (20mg, 0.12mmol) and Et ₃ N (33μl, 0.24mmol) in The mixture was 2 hours. The mixture was diluted with EtOAc. The mixture was washed with saturated aqueous NaHCO ₃ and brine, and dried over Na ₂ SO _4. The solvent was evaporated, and the silica gel column (with _{i- PrOH / CH 2 Cl 2 (} 2-10% gradient)) obtained residue was purified 174-3 (35mg, 75%).

A solution of 174-3 (35 mg, 0.03 mmol) in MeCN (0.4 mL) and HCl (40[mu]L; 4N in dioxane) was stirred at room temperature for 4 hr. The reaction was quenched by the addition of MeOH and solvent was evaporated. The residue was co-evaporated with toluene and the silica gel column (with a 4-10% gradient of _{MeOH / CH 2 Cl 2 ()} ) obtained was purified on a 174 (11mg, 56%). ESI-LCMS: m/z = 655 [M+H] ⁺ .

Example 101

At room temperature (17 ℃), under N ₂ atmosphere, was added DMTrCl to AA (300.0mg, 497.83μmol) in anhydrous pyridine (0.5mL) in a stirred solution of (337.36mg, 995.66μmol). The solution was stirred at 50 ° C to 60 ° C for 12 hours. The mixture was concentrated to dryness <RTI ID=0.0> The solution was washed with brine, dried over anhydrous MgSO ₄ The residue was purified on a EtOAc EtOAc (EtOAc:EtOAc)

Add DMAP (6.75 mg, 55.25 μmol), DCC to a stirred solution of 175-1 (100.00 mg, 110.50 μmol) in anhydrous pyridine (0.5 mL) at room temperature (18 ° C) under N ₂ atmosphere. (22.80 mg, 110.50 μmol) and n-octanoic acid (31.87 mg, 221.00 μmol). The solution was stirred at room temperature for 12 hours. The solution was concentrated to dryness under reduced pressure. The residue was purified on a silica gel column eluting with 15% EA to afford 175-2 (98.00 mg, 86.0%) as a white foam.

175-2 (90.00 mg, 87.28 μmol) was dissolved in 80% CH ₃ COOH (20 mL) at room temperature (16 ° C). The mixture was stirred at room temperature for 12 hours. The reaction was quenched with MeOH and the mixture was concentrated to dry. On silica gel column (5% MeOH in the DCM) is obtained residue was purified as a white solid of 175 (33.00mg, 88.7%). ESI-MS: m/z 427.2 [M+H] ⁺ .

Example 102

At 20 ℃, under N _2, the BB-1 (500.00mg, 0.87mmol) in dry pyridine was added TBSCl (236.5mg, 1.57mmol) (1mL ) in the stirred solution. The solution was stirred at 50 ° C to 60 ° C for 12 hours. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EA (50 mL). , And dried over anhydrous MgSO ₄ solution and with a _saturated brine solution NaHCO. The solution was filtered and the filtrate was concentrated to dryness. The residue was purified on a silica gel column to afford BB-2 (51.

TPSCl (368.65 mg, 1.25 mmol), DMAP (152.75 mg, 1.25 mmol) and TEA (126.52) were added to a stirred solution of BB-2 (430.00 mg, 625.15 mmol) in anhydrous MeCN (6 mL). Mg, 1.25 mmol). The mixture was stirred for 2 hours. NH ₄ OH (8 mL) was added, and the mixture was stirred for 3 hr. The mixture was extracted with EA (3 x 40 mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. In the silica gel column (with 25% EA of PE) and the residue was purified on a yellow foam of the BB-3 (500mg crude).

At room temperature (15 deg.] C), under N ₂ atmosphere, to a stirred solution added DMTrCl BB-3 (500mg crude product, 0.72 mmol) in dry DCM (7mL) in the via (365mg, 1.0mmol) and trimethyl pyridine (305mg, 2.5mmol) and AgNO ₃ (184mg, 1.08mmol). The mixture was stirred at room temperature for 12 hours. Add MeOH (5 ml). The mixture was filtered and the filtrate was concentrated to dry. The residue was dissolved in EA (50 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. On silica gel column (5% MeOH in the DCM) is obtained residue was purified as a white solid of BB-4 (500mg, 70.3% ).

BB-4 (1.00 g, 1.01 mmol) was dissolved in TBAF (5 mL, 1 M in THF) and stirred at room temperature for 30 min. The mixture was diluted with EA (100 mL). The mixture was washed with water and brine, and dried over anhydrous MgSO _4. The organic phase was concentrated to dryness. In the silica gel column (with 30% EA of PE) was obtained residue was purified as a white solid of BB (0.80g, 91.5%). ESI-MS: m/z 873.7 [M+1] ⁺ .

At room temperature (18 ℃), under N ₂ atmosphere, (, 114.29μmol 100.00mg) in anhydrous pyridine was added to BB (1.5mL) in a solution of DMAP (2.79mg, 22.86μmol), DCC (70.75mg, 342.88 μmol) and n-octanoic acid (49.45 mg, 342.88 μmol). The solution was stirred at room temperature for 12 hours. The solution was concentrated to dryness under reduced pressure. Was obtained as a white foam of 176-1 (95.00mg, 83.03%) in silica gel column (containing 15% EA of PE) and the residue was purified on.

176-1 (110.00 mg, 109.87 μmol) was dissolved in 80% CH ₃ COOH (25 mL) at room temperature (15 ° C). The mixture was stirred for 12 hours. The reaction was quenched with MeOH and the solution was concentrated to dry. On silica gel column (5% MeOH in the DCM) is obtained residue was purified as a white solid of 176 (30.00mg, 64.03%). ESI-MS: m/z 427.2 [M+H] ⁺ .

Example 103

In a similar manner to 143-1 , BB (250.0 mg, 276.25 μmol), (2S)-2-(t-butoxycarbonylamino)-3-methyl-butyric acid (360.11 mg, 1.66 mmol) was used. and TEA (83.86mg, 828.75μmol) preparation 177-1. 177-1 (white foam, 220.0 mg, 72.12%).

In a similar manner 143-2 of using 177-1 (230.00mg, 208.29μmol, 1.00 equiv) Preparation 177-2. 177-2 (white foam, 80.00 mg, 77.66%).

In a similar manner to 143 , 177 was prepared using 177-2 (100.00 mg, 200.20 μmol, 1.00 eq.). 177 (white solid, 56 mg, 59.57%). ESI-MS: m/z 400.0 [M+H] ⁺ , 4221.[M+Na] ⁺ ; 79.1[2M+H] ⁺ , 821.2[2M+Na] ⁺ .

Example 104

Compound 178

At 0 deg.] C (ice / water bath) to 178-1 (100mg, 0.175mmol) in dry CH of the ₃ CN (2.0mL) was added a stirred solution of N- methylimidazole (0.14mL, 1.4mmol). Was added a solution of 178-2 (220mg, 0.53mmol, was dissolved in 0.5mL CH ₃ CN), the (according Bondada, L, et al., ACS Medicinal Chemistry Letters, (2013 ) 4 (8):.. In the 747-751 General procedure preparation). The solution was stirred at 0 to 5 ° C for 1 hour, followed by stirring at room temperature for 16 hours. The mixture was cooled to 0 to 5 ° C, diluted with EA then water (5 mL). Solution, NaHCO ₃ and washed with 1.0M aqueous citric acid and saturated brine, and dried over MgSO _4. The residue was purified on EtOAc (EtOAc: EtOAc (EtOAc)

The 178-3 (56mg, 0.0585mmol) was dissolved in ₃ CN (0.7mL) in dry CH, and was added in dioxane (44μL, 0.176mmol) 4N HCl at 0 to the 5 ℃. The mixture was stirred at room temperature for 2 hours. Dioxane (20 μL) containing 4N HCl was added. The mixture was stirred at room temperature for 2 hours. Anhydrous EtOH (100 μL) was added. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). In Silica (10g column, with a gradient of 1-7% _{MeOH / CH 2 Cl 2 ()} ) and the residue was purified lyophilized to obtain a white foam of 178 (27.6mg, 69%). ESI-LCMS: m/z = 685.2 [M+H] ⁺ .

Example 105

Compound 179

At 0 ℃, to 179-1 (1.92g, 27.3mmol), PPh 3 (1.43g, 54.7mmol), EtOH (0.25g, 54.7mmol) in dry dioxane by (20mL) in a stirred solution of DIAD (1.11 g, 54.7 mmol) was added dropwise. The solution was stirred at 25 ° C for 15 hours. The reaction was quenched with water and extracted with EtOAc. The mixture was washed sequentially with water and brine. The organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness EtOAc ( EtOAc m .

TEA (0.59 g, 58.8 mmol) and DMTrCl (0.99 g, 29.4 mmol) were added to a stirred solution of 179-2 (1.43 g, 19.6 mmol) in DMF (15 mL). The solution was stirred at 25 ° C for 12 hours. The mixture was treated with MeOH (1 mL) and diluted with EtOAc. Wash the solution with water and brine. The organic layer was dried over anhydrous NaSO _4, and concentrated to dryness. The residue was purified with EtOAc EtOAc m .

(, 1.1mmol 1.13g) was added TBDPSCl (0.91g, 3.3mmol) and AgNO ₃ (0.61g, 3.3mmol) to 179-3 in anhydrous pyridine (10 mL) in the stirred solution. The mixture was stirred at 25 ° C for 15 hours. The solid was removed by filtration and the filtrate was diluted with EA (50 mL). The solution was washed with brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc )

At -78 ℃, to 179-4 (1.22g, 1.0mmol) was added Cl ₂ CHCOOH (0.6mL) in of anhydrous DCM (15mL) stirred solution. The mixture was stirred at -20 ° C for 1 hour. With saturated aqueous NaHCO ₃ The reaction was quenched and extracted with DCM. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

At 0 ℃, to 179-5 (0.52g, 0.5mmol) in dry DCM (15mL) and pyridine (0.21g, 2.5mmol) in the stirred solution was added dropwise containing Tf ₂ O (0.30g, 1.0mmol ) DCM (1 mL). The mixture was stirred at 0 ° C for 15 minutes. The reaction was quenched with ice water. The organic layer was separated and washed with water. The organic layer was dried over anhydrous Na ₂ SO _4, and concentrated to obtain a low pressure as a yellow foam of 179-6 (442mg crude).

Was added to a stirred solution of the 179-6 (442mg, 0.4mmol) in dry DMF (5mL) was NaN ₃ (131mg, 2.0mmol). The mixture was stirred at room temperature for 12 hours. The reaction was quenched with water and EtOAc (EtOAc) And dried over Na ₂ SO ₄ organic layer was washed with water. The organic phase was evaporated to dryness under reduced pressure. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc )

Was stirred at 80 ℃ 179-7 (352mg, 0.35mmol) and NH ₄ F (392mg, 10.6mmol) in a mixture of MeOH (10 mL) in the 12 hours. The mixture was cooled to room temperature. The solids were removed by filtration. The solvent was concentrated under reduced pressure. The residue was purified on EtOAc EtOAc ( EtOAc ) By preparative HPLC (containing 0.1% NH ₄ HCO ₃ of water and CH ₃ CN) purification of the crude product was obtained as a white solid of 179-8 (71.5mg, 32%). MS: m/z 641 [M + H] ⁺ .

By evaporation with toluene so 179-8 (64mg, 0.1mmol) and the mixture was dry-bis (acyl pivaloyl oxymethyl) after phosphate, which was dissolved in CH ₃ CN (1mL) and cooled to 0 ℃. BocCl (40 mg, 0.15 mmol) and NMI (40 μL, 0.5 mmol) were added. The mixture was stirred at 0 ° C for 2 hours. Add EtOAc, and the mixture was washed with 0.5N aqueous citric acid, washed with saturated aqueous NaHCO ₃ and brine, then dried over Na ₂ SO _4. The solvent was removed, and the silica gel column (containing 3% i -PrOH having the CH ₂ Cl ₂₎ on the residue obtained was purified 179-9 (38mg, 40%).

It was stirred at rt 179-9 (30mg, 0.03mmol) in CH ₃ CN (0.3mL) and HCI; solution (30μL 4N in dioxane) was of 100 minutes. The reaction was quenched with EtOH and the mixture was evaporated. In the silica gel column (3-10% gradient _{/ CH 2 Cl 2 (i-} PrOH)) The crude residue was purified on obtaining 179 (10mg, 50%). ESI-LCMS: m/z = 671 [M+H] ⁺ .

Example 106

To BB (100mg, 0.114mmol) in dry solution of ₃ CN (1mL) bis -SATE- amine phosphate (62.2mg, 0.14mmol) in CH The solution was added in CH ₃ CN (2mL), followed 0 CH ₃ CN (0.25 M; 0.56 mL, 0.14 mmol) containing 5-ethylthio-1H-tetrazole was added dropwise at 5 °C. The mixture was stirred at 0 to 5 ° C for 2 hours under Ar. A solution of 77% m-CPBA (49 mg, 0.22 mmol) in DCM (1 mL) was added and the mixture was stirred at 0 to 5 ° C for 2 hours. The mixture was diluted with EtOAc (50mL), with 1.0M citric acid, washed with saturated NaHCO ₃ and brine, and dried over MgSO _4. The mixture was filtered and the solvent was evaporated in vacuo. In Silica (10g column with EA / hexanes (10-100% gradient)) to obtain the residue was purified as a white solid of 180-1 (72mg, 50.8%).

The 180-1 (72mg, 0.056mmol) was dissolved in ₃ CN (1.0mL) in dry CH, and added 4N HCl in dioxane of (87μL, 0.35mmol) at 0 to 5 ℃. The mixture was stirred at room temperature for 2 hours. Intermediate 180-2 was observed by LCMS. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). The residue obtained was redissolved in 80% HCOOH (2 mL). The mixture was stirred at room temperature for 4.5 hours. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). Anhydrous EtOH (3 x 5 mL) was added. The residue was dissolved in _{50% CH 3 CN / H 2} O in, ₃ CN and H ₂ O CH purification on reverse phase HPLC (C18), and lyophilized to obtain a white foam of 180 (19.2mg). ESI-LCMS: m/z = 666.2.[M+H] ⁺ , 1337.25 [2M+H] ⁺ .

Example 107

In the same manner as 169-4 , in the same manner, from BB (100 mg, 0.114 mmol) and bis(t-butoxycarbonyloxymethyl)phosphate (83 mg, 0.35 mmol) with DIPEA (126 μL, 0.69) 181-1 (98 mg, 72.6%) was prepared from EtOAc (EtOAc) (EtOAc)

In the same manner as in the 146, since 181-1 (98mg, 0.083mmol) Preparation 181 (30.2mg, 60%). ESI-LCMS: m / z = 609.15 [M + H] +, 1217.3 [2M + H] +.

Example 108

Compounds 182 , 182aa , 182ab and 183 were prepared as described in PCT Publication No. WO 2014/96680, published June 27, 2014. 182: ESI-LCMS: m / z 554.0 [M + H] +; 182aa and 182ab: The faster eluting diastereomer thereof ^{- 31 P NMR 67.1, LC /} MS 552 [M-1]. The slower-dissolving diastereomer - ³¹ P NMR 67.9, LC/MS 552 [M-1]. 183 : ESI-MS: m/z 576.9 [M+H] ⁺ .

Example 109

Compound 186-201

Compound 186-201 was prepared as described in PCT Publication No. WO 2014/96680, published June 27, 2014. 186 : ESI-LCMS: m/z 593.0 [M+H] ⁺ . 187: ESI-LCMS: m/z 614.1 [M+H] ⁺ . 188: ESI-LCMS: m/z 582.1 [M+H] ⁺ . 189: ESI-LCMS: m/z 596.1 [M+H] ⁺ . 190: ESI-LCMS: m/z 672.0 [M+H] ⁺ . 191: ESI-LCMS: m/z 589.0 [M+H] ⁺ . 192: ESI-LCMS: m/z 606.0 [M+H] ⁺ . 193: ESI-LCMS: m/z 604.1 [M+H] ⁺ . 194: ESI-LCMS: m / z 568 [M + H] +, 590 [M + Na] +. 195: ESI-LCMS: m/z 650 [M+H] ⁺ . 196: ESI-LCMS: m/z 578.0 [M+Na] ⁺ . 197: ESI-MS: m/z 633.1 [M+H] ⁺ . 198: ESI-LCMS: m / z 604 [M + Na] +, 582 [M + H] +. 199: ESI-LCMS: m/z 582.0 [M+H] ⁺ . 200: ESI-LCMS: m/z 618 [M+Na] ⁺ . 201: ESI-LCMS: m/z 568.1 [M+H] ⁺ .

Example 110

A method of preparing compound 204 is provided in WO 2010/015643 filed on Aug. 4, 2009.

Example 111

Compound 206

206-1 (1.0g, 3.53mmol) in dry pyridine and co-evaporated with three times to remove the H ₂ O. At 0 ℃, 206-1 in the ice-cold solution of anhydrous pyridine (9mL) was added dropwise pyridine (3mL) containing TsCl (808mg, 4.24mmol) of, and the mixture was stirred at 0 ℃ 18 hours. The reaction monitored by LCMS, and then quenched with ₂ O H. After concentration at low pressure, the residue was dissolved in EA (50 mL). The solution was washed with a saturated solution of NaHCO ₃ and brine. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The filtrate was evaporated to a low pressure and by silica gel column chromatography (1% MeOH in the DCM) is obtained residue was purified as a white solid of 206-2 (980mg, 63%).

In acetone (10 mL) was added in the NaI (1.01g, 6.73mmol) to 206-2 (980mg, 2.24mmol), and the mixture was heated to reflux overnight. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated at a low pressure. The residue was dissolved in EA (50 mL). Solution was washed with brine, and dried over anhydrous Na ₂ SO _4. The solution was evaporated under reduced pressure and EtOAc EtOAc m .

To a solution of < RTI ID=0.0># < /RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The mixture was stirred overnight and monitored by LCMS. The reaction was quenched with saturated NaHCO _3, and (3 × 50 mL) and extracted with EA. The organic phase was dried and filtered over anhydrous Na ₂ SO _4. The filtrate was evaporated under reduced pressure and the residue was purified mjjjjjjjjjjj

Add NEt _{3 to an} ice-cold solution of 206-4 (250 mg, 0.94 mmol) in anhydrous MeCN (5 mL). 3HF (151 mg, 0.94 mmol) and NIS (255 mg, 1.13 mmol). The mixture was stirred at room temperature for 3 hours and checked by LCMS. The reaction was, and extracted with EA (3 × 50mL) with saturated Na ₂ S ₂ O ₃ and saturated NaHCO ₃ solution was quenched. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and evaporation under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

To a solution of 206-5 ( 270 mg, 0.65 mmol The mixture was stirred at room temperature for 4-5 hours and checked by LCMS. The mixture _diluted with CH Cl _2, and washed with saturated NaHCO ₃ solution and brine. The organic layer was evaporated to a low pressure and by silica gel column chromatography (inclusive of PE 20% EA) to afford the residue obtained as a solid of 206-6 (290mg, 86%).

To a solution of 206-6 (900 mg, 1.74 mmol) in EtOAc (EtOAc) The mixture was stirred at 90-100 ° C for 48 hours. The mixture was diluted with EA (100 mL) and washed with brine. The organic layer was evaporated to a low pressure and by silica gel column chromatography (inclusive of PE 20% EA) was obtained residue was purified 206-7 (500mg, 56%) of a solid.

At room temperature to 206-7 (500mg, 0.98mmol) in dry CH of the ₃ CN (5mL) was added TPSCl (741mg, 2.45mmol), DMAP (299.6mg, 2.45mmol) and NEt ₃ (248mg, 2.45 mmol) and the mixture was stirred overnight. Followed by containing the NH THF ₃ (5mL) processing the mixture, followed by stirring for 30 minutes. The mixture was diluted with EA (100 mL). The solution was washed with a 0.5% AcOH solution. The organic solvent was dried over anhydrous MgSO _4, and concentrated under low pressure. The crude product was purified by EtOAc EtOAc (EtOAc) ESI-MS: m/z 509 [M+H] ⁺ .

206-8 (80 mg, 0.16 mmol) was dissolved in n-butylamine (3 mL). The mixture was kept at room temperature overnight and evaporated. The residue was crystallized from methanol to afford 206 (30 mg). The mother liquor was purified by RP HPLC on a Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of 0 to 30% methanol in 50 mM triethylammonium acetate buffer (pH 7.5) was used to dissolve. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess buffer to give an additional 206 (13 mg). 206 (total yield 43 mg, 73%). MS: m/z 299.7 [M-1] ^- .

Example 112

The 207-1 (30mg, 0.1mmol) was dissolved in a mixture of CH ₃ CN (2mL) and N- methylimidazole (200 L) of the. Chlorophosphate (100 mg, 0.3 mmol) was added and the mixture was kept at room temperature for 5 days. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The phosphonium amide was separated by gelatin chromatography (gradient from 3% to 10% methanol in DCM). The corresponding fractions were concentrated and re-purified on a Synergy 4 micron Hydro-RP column (Phenominex) by RP HPLC. Dissolution was carried out using a linear gradient of 3% to 95% methanol in DCM (containing 0.1% formic acid). 207 (9 mg, 16%) was obtained as a mixture of Rp and Rs isomers. MS: m/z 562.1 [M-1] ^- .

Example 113

Compound 211

DAST (31.9 g, 198 mmol) was added dropwise to a solution of 211-1 (23.0 g, 39.5 mmol) in anhydrous toluene (200 mL), and the solution was stirred at -78 ° C for 3 hours. ₃ The mixture was quenched with saturated NaHCO, and extracted with EA (2 × 200mL) and dried over anhydrous Na ₂ SO _4. The solution was concentrated to dryness at low pressure. The residue was purified on a silica gel column eluting with 50% EA to afford 211-2 (16.5 g, 71%) as a yellow foam.

It was stirred at 70 ℃ 211-2 (16.0g, 27.4mmol) in a mixture of 12 hours and NH ₄ F (3.0g, 82.2mmol) in methanol (100mL). The reaction was cooled and the salt was removed by filtration. The filtrate was concentrated to dryness at low pressure. The residue was purified on a EtOAc EtOAc EtOAc (EtOAc)

To a solution of 211-3 (4.1 g, 15.2 mmol), PPh ₃ (8.0 g, 30.4 mmol), imidazole (2.1 g, 30.4 mmol) and pyridine (18.2 mL) in anhydrous THF (40 mL) stirred suspension was added dropwise I ₂ (5.8g, 22.8mmol) in (20mL) in a solution of THF. The mixture was stirred at room temperature for 12 hours. The reaction was quenched with MeOH (100 mL)EtOAc The residue was purified on a EtOAc EtOAc EtOAc (EtOAc) ESI-MS: m/z 381.1 [M+1] ⁺ .

DBU (2.1 g, 14 mmol) was added to a stirred solution of 211-4 (2.5 g, 0.7 mmol) in dry THF (3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with HOAc and diluted with 2-Me-THF. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to dryness and a low pressure. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc:EtOAc

At 0 ℃, to 211-5 (800mg, 3.17mmol) was added in dry CH TEA˙3HF (510mg, 3.17mmol) and NIS (785mg, 3.49mmol) in the ₃ CN (10mL) stirred solution. The mixture was stirred for 30 minutes, gradually warmed to room temperature, and stirred for 1 hour. The mixture was quenched with a saturated solution of NaHCO ₃ and Na ₂ S ₂ O ₃ solution, and extracted with EA (2 × 20mL). The organic layer was dried over anhydrous Na ₂ SO _4, concentrated to dryness and a low pressure. The residue was purified on a EtOAc EtOAc EtOAc (EtOAc)

BzCl (507 mg, 3.59 mmol) was added to a stirred solution of 211-6 (650 mg, 1.63 mmol) in pyridine (3 mL), and stirred at room temperature for 12 hr. The mixture was quenched with water and concentrated to dryness. The residue was purified on a EtOAc EtOAc ( EtOAc: EtOAc )

Tetrabutylammonium hydroxide (9 mL, 54-56% aqueous solution, 72 mmol) was neutralized with TFA (1.5 mL) to pH ~ 4 and mixture was added to 211-7 (375 mg, 0.75 mmol) in DCM ( 9mL ) In the solution. The m-chloroperbenzoic acid (924 mg, 60-70%, 3.75 mmol) was added portionwise with vigorous stirring, and the mixture was stirred overnight. The mixture was washed with brine, dried over magnesium sulfate The residue was purified by column chromatography eluting with EtOAc ( EtOAc ) ESI-MS: m/z 393.1 [M+1] ⁺ .

(20mL) was treated with _{7N NH 3 ˙MeOH 211-8 (120mg,} 0.24mmol), and stirred for 5 hours. The mixture was concentrated to dryness under reduced pressure. In the silica gel column (with DCM 15% of propan-2-ol) obtained residue was purified on a white solid of 211 (53mg, 60.2%). ESI-MS: m/z 288.8 [M+1] ⁺ .

Example 114

Add AgNO ₃ (0.22 g, 1.29 mmol), trimethylpyridine (0.15 g, 1.29 mmol) and MMTrCl to a solution of 212-1 (0.47 g, 0.65 mol) in DCM (3 mL). 0.3 g, 0.974 mmol). The mixture was stirred overnight at room temperature. The mixture was filtered, and _saturated aqueous brine and filter with NaHCO. The organic layer was separated, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column silica gel was obtained as a white solid of 212-2 (0.55,85%).

To a solution of 212-2 (0.5 g, 0.5 mmol) EtOAc. The mixture was stirred at 95 ° C for 72 hours. The mixture was diluted with EA and washed with water and brine. The organic phase was dried over MgSO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

Containing stirred 212-3 (0.3g, 0.3mmol) of NH ₃ / MeOH (30mL) 18 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was purified mjjjjjjjjjj ESI-LCMS: m/z 890.5 [M+H] ⁺ .

(161mg, 0.16mmol) in dry CH added N- methylimidazole of ₃ CN (2.0mL) was stirred at 0 to 5 ℃ (ice / water bath) was added to a solution of 212-4 (118μL, 2.87mmol), followed by was added a solution of 212-5 (186mg, 0.54mmol, was dissolved in 2mL CH ₃ CN in). The solution was stirred at 0 to 5 ° C for 4 hours. The mixture was diluted with EA and water (15 mL) was added. The solution was washed with H ₂ O, 50% aqueous citric acid and brine. The organic layer was separated, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to obtain a residue, which silica gel (with zero to 40% EA / hexanes) to obtain the purified (82.6 mg) and the slower eluting isomer of isomers from the fast dissolving 212-6212-7 ( 106 mg).

The 212-6 (82.6mg, 0.07mmol) was dissolved in ₃ CN (0.5mL) in dry CH, and was added in dioxane (35μL) 4N HCl at 0 to the 5 ℃. The mixture was stirred at room temperature for 1 hour, and anhydrous EtOH (100 μL) was added. The solvent was evaporated at room temperature and co-evaporated 3 times with toluene. The residue was dissolved in _{50% CH 3 CN / H 2} O in water and acetonitrile and purified on reverse phase HPLC (C18), followed by lyophilization to obtain 212a (19.4mg). ESI-LCMS: m/z = 655.2 [M+H] ⁺ , 653.15 [MH] ^- .

The 212-7 (100mg, 0.083mmol) was dissolved in anhydrous CH ₃ CN (0.5mL), and was added in dioxane (50μL) 4N HCl at 0 to the 5 ℃. Following the procedure for obtaining 212a , 212b (31.8 mg) was obtained. ESI-LCMS: m / z = 655.2 [M + H] +, 653.1 [MH] -.

Example 115

Compound 213

At 0 ℃, under N _2, to a nucleoside (300mg, 1.09mmol) and proton sponge (467mg, 2.18mmol) in dry the CH ₃ CN (5mL) was added dropwise phosphorous oxychloride (330mg, 2.18 mmol) in the ₃ CN (1mL) was in dry CH. The mixture was stirred at 0 ° C for 30 min, and (S)-2-aminopropionic acid ethyl ester hydrochloride (998 mg, 6.52 mmol) and triethylamine (1.5 mL, 10.87 mmol). The mixture was stirred at 30 ° C overnight. The reaction was quenched with EtOAc (EtOAc) The organic layer was concentrated under low pressure, and the residue was purified by reverse phase HPLC was obtained as a white solid of 213 (20mg, 3%). ESI-LCMS: m/z 535 [MF] ⁺ .

Example 116

The nucleoside (140 mg, 0.42 mmol) was dissolved in n-butylamine (0.5 mL). The mixture was kept at room temperature for 2 hours, followed by evaporation of the amine. The residue was dissolved in EtOAc, and the organic layer was washed twice with 10% citric acid, dried over Na ₂ SO ₄ and evaporated. The residue was purified by hydrazine column chromatography (linear gradient from 0% to 12% methanol in 10 column volume DCM). The fractions containing the product were concentrated and treated with 80% HCOOH for 1 hour at room temperature. The mixture was evaporated to dryness and suspended in CH ₃ CN in. The precipitate was isolated, with CH ₃ CN (1mL) was washed and dried to obtain 214 (27mg, 50%). MS: m/z 326.5 [M-1] ^- .

Example 117

Compound 216

At 0 ℃, the (80 mL) in a solution of 216-1 (3.0g, 18.0mmol) and POCl ₃ (1.35g, 9.0mmol) in DCM was added dropwise containing TEA (3.6g, 36.0mmol) of DCM ( 20mL). The mixture was stirred at 0 ° C for 2 hours. A solution of pentafluorophenol (1.65 g, 9.0 mmol) and TEA (0.9 g, 9.0 mmol) in DCM (20 mL). After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was washed by TBME and filtered. The filtrate was concentrated under low pressure and by silica gel chromatography (20% EA of containing PE) was obtained residue was purified 216-2 (2.7g, 62.7%) of a white solid. ESI-MS: m/z 491.1 [M+1] ⁺ .

To 1-((3aR,4R,6S,6aS)-6-fluoro-6-(hydroxymethyl))-2-methoxy-3a-methyltetrahydrofuran [3,4-d at 0 °C [1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.47 mmol) in anhydrous THF (2 mL) A solution of t-BuMgCl (0.46 mL, 1 M in THF) was added dropwise. The mixture was stirred at room temperature for 40 minutes and cooled to 0 °C. A solution of 216-2 (462 mg, 0.94 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Quenched with H ₂ O mixture and extracted with EA. The organic layer was dried over Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified on a EtOAc EtOAc ( EtOAc: EtOAc )

216-3 (230 mg, 0.37 mmol) was dissolved in 80% aqueous HCOOH (20 mL), and the mixture was stirred at room temperature for 24 hr. Remove solvent at low pressure. The residue was purified on a silica gel column to afford crude material, which was purified by EtOAc (HCOOH) to afford 216 (75 mg, 33%) as a mixture of two P-isomers. ESI-TOF-MS: m/z 583.0 [M+H] ⁺ .

Example 118

The 218-1 (30mg, 0.1mmol) was dissolved in a mixture of CH ₃ CN (2mL) and N- methylimidazole (200 L) of the. Chlorophosphate (100 mg, 0.3 mmol) was added and the mixture was kept at 40 ° C overnight. The temperature was raised to 65 ° C and heated for 1 hour. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The azido-amino phosphate was purified by RP HPLC on a Synergy 4 micron Hydro-RP column (Phenominex). The dissolution was carried out using a linear gradient of 30 to 100% methanol in 50 mM triethylammonium acetate buffer (pH 7.5). Azido - amine phosphate (8mg) was dissolved in pyridine _{/ Et 3 N (3mL, 8} : 1 v / v) and cooled to 0 ℃. H ₂ S gas was bubbled through the solution for 10 minutes and the reaction was held at room temperature for 1 hour. The solvent was evaporated and the residue was separated by EtOAc. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove the buffer to obtain 218 (1.2 mg) as a mixture of Rp and Rs isomers. MS: m/z 544.1 [M+1] ⁺ .

Example 119

Compound 219

In dry CH ₃ CN (2L) to IBX (133.33g, 476mmol) at room temperature was added a solution of 219-1 (100.0g, 216mol). The mixture was refluxed and stirred for 12 hours. The mixture was filtered, and the filtrate was evaporated, mjjjjjjjj

219-2 (50.0g, 108.70mmol) and co-evaporated twice with dry toluene to remove H ₂ O. Magnesium bromide bromide (800 mL, 400.0 mmol) was added dropwise to a solution of 73-2 in THF (500 mL) over 20 min. The mixture was stirred at -78 ° C for about 10 minutes. When the starting material is exhausted, the ice-acetone cooling bath is removed. Under stirring the mixture was quenched with saturated NH ₄ Cl solution, then warmed to room temperature. The mixture was extracted with EA, filtered over celite and washed with brine. The combined The organic phase was dried over anhydrous Na ₂ SO _4, filtered, and concentrated to obtain a dark yellow low pressure oil of the crude product 219-3 (48.0g, yield: 90.8%).

The 219-3 (200.0g, 411.52mmol) was dissolved in anhydrous CH ₂ Cl ₂ (2000mL), followed by addition of DMAP (100.41g, 823.05mmol) and Et ₃ N at room temperature (124.94 g, 1.23mol). The mixture was treated with benzamidine chloride (173.46 g, 1.23 mol) at 0 °C. After stirring at room temperature for 12 hours, quenched with H ₂ O reaction. The combined aqueous phases were extracted with DCM. The combined The organic phase was dried over Na ₂ SO _4, filtered and evaporated to dryness under reduced pressure to give a black oil. The oil was purified by column chromatography eluting with EtOAc EtOAc EtOAc Filtered and the residue was triturated CH ₃ OH. The filter cake was concentrated in vacuo to afford 219-4 (30.0 g, 36.4%) as a white solid.

Uracil (34.17g, 305.08mmol) and co-evaporated twice with dry toluene to remove H ₂ O. N, O-BSA (123.86 g, 610.17 mmol) was added to a stirred suspension of uracil in anhydrous MeCN (150 mL). The mixture was refluxed for 1.5 hours and then cooled to room temperature. Add 219-4 (90g, 152.54mmol, which is co-evaporated twice with dry toluene to remove H ₂ O). TMSOTf (237.05 g, 1.07 mol) was then added at room temperature. The mixture was heated to 70 ° C, then stirred overnight and then monitored by LCMS. The mixture was cooled to room temperature, and washed with saturated NaHCO ₃ solution was quenched. The solution was extracted with EA. The organic layer was dried over Na ₂ SO _4, then concentrated under low pressure. The residue was purified by EtOAc ( EtOAc ) elut elut

Processing 219-5 (50g, 86.21mmol) at room temperature with the containing NH MeOH ₃ (1L), followed by stirring for 48 hours. The mixture was concentrated under reduced pressure and purified EtOAc EtOAcjjjjjjj

TsOH ̇H ₂ O (1.13 g, 5.9 mmol) was added to a solution of cyclopentanone (100 g, 1.189 mmol) and trimethyl orthoformate (150 mL) in MeOH (600 mL). minute. With NaOMe (0.32g, 5.9mmol) and H ₂ O The reaction was quenched and extracted by n-hexane solution. The organic layer was dried over anhydrous Na ₂ SO _4, then concentrated under low pressure. The acetal dicyclopentyldimethoxysilane and 219-6 (20g, 74.63mmol) was dissolved in DCE (200mL), followed by (, 3.73mmol 0.71g) was treated with TsOH˙H ₂ O. The mixture was stirred at 50 ° C for 12 hours and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

219-7 (20.0g, 0.06mol) in dry pyridine and co-evaporated three times to remove the H ₂ O. TsCl (22.8 g, 0.12 mol) was added to EtOAc EtOAc (EtOAc)EtOAc . The reaction was quenched with H ₂ O, and extracted with EA. The organic phase was dried over anhydrous NaSO ₄ and evaporated a low pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc )

NaI (31.0 g, 0.2 mol) was added to a solution of EtOAc ( EtOAc) ( EtOAc ) The mixture was quenched with a saturated Na ₂ S ₂ O ₃ solution and extracted with EA. The organic phase was dried over anhydrous Na ₂ SO _4, and the low pressure evaporator. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc

Add CuBr (4.9 g, 0.034 mol), i- Pr ₂ NH (13.6 g, 0.135 mol) to 219-9 (30.0 g, 0.068 mol) of dioxane (60 mL) in a sealed tube under N ₂ . And (CH ₂ O) _n (5.1 g, 0.17 mol). The mixture was heated under reflux for 16 hours. Mixture was diluted with EtOAc, and washed with saturated NH ₄ Cl solution and with brine. The solution was dried over anhydrous MgSO.sub. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc

(80%) of H ₂ O treated 219-10 (10g, 21.83mmol) at room temperature containing HCOOH. The solution was stirred at 60 ° C for 2 hours and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

219-11 (5 g, 12.79 mmol) was dissolved in dry MeOH (100 mL)EtOAc. The solution was stirred at 60 ° C for 36 hours. _Mixture was quenched with CO, and then concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H-NMR (CDCl ₃ , 400 MHz) δ = 7.29 (d, J = 8 Hz 1H), 6.10 (s, 1H), 5.71 (d, J = 8.0 Hz 1H), 5.18 (t, J = 6.4 Hz, 1H) ), 4.79-4.84 (m, 1H), 4.61 (d, J = 8.0 Hz, 2H), 4.39 (s, 1H), 3.45 (s, 1H).

Under N _2, to 219-12 (1.5g, 5.68mmol) in dry was added NIS (1.66g, 7.39mmol) and TEA˙3HF (0.73g, 4.55mmol) of in MeCN (15mL) solution of ice. The mixture was stirred at room temperature for 1 hour. The reaction was, and extracted with EA (3 × 100mL) washed with saturated NaHCO ₃ and ₂ SO ₃ solution was quenched with saturated Na. The organic phase was dried over anhydrous Na ₂ SO _4, evaporated to dryness and a low pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc

At room temperature to 219-13 (1g, 2.44mmol) in anhydrous DCM's (10 mL) was added DMAP (0.60g, 4.88mmol) and Et ₃ N (0.74g, 7.32mmol) at room temperature. The mixture was treated with benzamidine chloride (0.79 g, 5.61 mmol) at 0 ° C, then stirred at room temperature for 3 hr. The reaction was quenched with water and extracted with EtOAc EtOAc. The organic phase was concentrated with EtOAc ( EtOAc ) EtOAc .

Bu ₄ NOH (55% in H ₂ O, 13.74 mL) was treated with TFA (pH = 3-4). The mixture was cooled to room temperature. m-CPBA (80%, 1.57 g, 7.28 mmol) was added to a solution of 219-14 (0.9 g, 1.46 mmol) in DCM (9 mL). The mixture was stirred at 25 ° C for 48 h. The mixture was washed with _saturated aqueous NaHCO. The column was passed through an anhydrous Al ₂ O ₃ column, and the solution was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

The 219-15 (0.25g, 0.49mmol) was dissolved in NH ₃ / MeOH in (5mL, 7M), and at room temperature, under N _2, the mixture was stirred for 24 hours. The mixture was concentrated under reduced pressure at EtOAc ( EtOAc ) EtOAc ( EtOAc ) ¹ H-NMR (CD ₃ OD, 400 MHz) δ = 7.83 (d, J = 8 Hz 1H), 6.29 (s, 1H), 5.67 (d, J = 6.0 Hz 1H), 5.12 (t, J = 6.8 Hz, 1H), 4.99-5.01 (m, 1H), 4.38 (d, J = 19.6 Hz 1H), 3.74 - 3.81 (m, 2H), 3.35 (s, 1H).

219-16 (100mg, 0.33mmol) was coevaporated three times with toluene to remove the H ₂ O. At 0 ℃, was added 219-C (216.5mg, 0.66mmol) in MeCN mixture 219-16 (100mg, 0.33mmol) in MeCN (1.0 mL) and NMI (271mg, 3.3mmol) in the stirred solution of ( Solution in 0.5 mL). The mixture was stirred at room temperature overnight then quenched with water. The mixture was diluted with EA (20mL), and the organic layer was washed with water and brine, and dried over anhydrous Na ₂ SO _4. The organic phase was concentrated to low pressure, and the obtained crude product was silica gel column (with 5% i -PrOH of DCM) and the residue was purified. Preparative HPLC (containing 0.1% HCOOH water and MeCN) obtained crude product was purified as a white solid of 219 (35.6mg, 19.0%). ESI-LCMS: m/z 592 [M+Na] ⁺ .

TEA (1.33 g, 13.16 mmol) was added dropwise to a stirred solution of 219-A (2.0 g, 13.16 mmol) and phenol (1.22 g, 13.16 mmol) in anhydrous DCM (100 mL) Solution in DCM (20 mL). The mixture was gradually warmed to room temperature and then stirred for 2 hours. The solution was re-cooled to -78 ° C, and EtOAc (2.20 g, 13.16 mmol). 26.29 mmol) of DCM (20 mL). The mixture was gradually warmed to room temperature and then stirred for 2 hours. The organic solvent was removed at low pressure and the residue was dissolved in methyl-butyl ether. The precipitate was filtered and the filtrate was concentrated under reduced pressure. Purification on silica gel column (dry DCM) to obtain the residue as a colorless oil of 219-C (0.9g, 22.3% ).

Example 120

Anhydrous nucleoside (0.05 mmol) was dissolved in a mixture of PO (OMe) ₃ (0.7 mL) and pyridine (0.3 mL). The mixture was evaporated under vacuum at 42 °C for 15 minutes and then cooled to room temperature. N-methylimidazole (0.009 mL, 0.11 mmol) and POCl ₃ (0.009 mL, 0.11 mmol) were added sequentially. The mixture was kept at room temperature for 20-40 minutes and the formation of 220 was monitored by LCMS. The reaction was quenched with water and separated on a Synergy 4 micron Hydro-RP column (Phenominex) by RP HPLC. A linear gradient of 0 to 30% methanol in 50 mM triethylammonium acetate buffer (pH 7.5) was used to dissolve. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess buffer. MS: m/z 396.5 [M-1] ^- .

Example 121

A solution of 223-1 (16.70 g, 0.363 mol) and TEA (36.66 g, 0.363 mol) in CH ₂ Cl ₂ (150 mL) was added dropwise to a mixture containing POCl ₃ (55.65 g) at -78 °C , 0.363 mol) in a stirred solution of DCM (100 mL). After the mixture was stirred at room temperature for 2 hr, triethylamine hydrochloride was filtered and washed with CH ₂ Cl ₂ (100 mL). The filtrate was concentrated at low pressure and the residue was distilled using a cow-head fraction collector under high vacuum (about 10 mm Hg). 223-2 (30.5 g, 50% yield) was obtained as a colorless liquid between 45 ° C (distill. ^{1 H-NMR (400MHz, CDCl} 3) δ = 4.44 (dq, J = 10.85,7.17Hz, 2 H), 1.44-1.57 (m, 3 H); 31 P-NMR (162MHz, CDCl 3) δ = 6.75 (br.s., 1P).

At room temperature to 227-A (93mg, 0.15mmol) in CH of the ₂ Cl ₂ (1mL) was added to a stirred suspension of TEA (61mg, 0.15mmol). The mixture was cooled to -20 ° C and then treated dropwise with a solution of 223-2 (35 mg, 0.21 mmol) over a period of 10 min. The mixture was stirred at this temperature for 15 minutes and then treated with NMI (27 mg, 0.33 mmol). The mixture was stirred at -20 ° C and then slowly warmed to room temperature. The mixture was stirred overnight. The mixture was suspended in EtOAc (15 mL)EtOAc. The solution was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjj

A solution of 223-3 (60 mg, 0.085 mmol) in 80% aqueous AcOH (2 mL) was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure and by silica gel column (DCM / MeOH = 50/1 eluting) and the residue was purified by preparative HPLC to obtain a white solid of 223 (23mg, 62%). ESI-MS: m/z 436.3 [M+H] ⁺ .

Example 122

223-2 prepared using the analogous procedure, using isobutanol (23.9g, 322.98mmol) and POCl ₃ (49.5g, 322.98mmol) of a solution prepared 224-2. 224-2 (26 g, 42% yield) was obtained as a colourless liquid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 4.10 (dd, J = 9.04, 6.39 Hz, 2 H), 2.09 (dq, J = 13.24, 6.67, 6.67, 6.67, 6.67 Hz, 1 H), 1.01 ( d, J = 6.62 Hz, 6 H); ³¹ P-NMR (162 MHz, CDCl ₃ ) δ = 7.06 (br.s., 1P).

At room temperature, in the CH ₂ Cl ₂ (3mL) was stirred into 227-A (310mg, 0.5mmol), was added TEA (202mg, 2mmol). The mixture was cooled to -20 ° C then treated with 224-2 (134 mg, 0.7 mmol). The mixture was stirred at this temperature for 15 minutes and then treated with NMI (90 mg, 1.1 mmol). The mixture was stirred at -20 ° C for 1 hour, then slowly warmed to room temperature overnight. The mixture was suspended in EtOAc (15 mL)EtOAc. The organic phase was concentrated under reduced pressure. EtOAc EtOAc m .

A solution of 224-3 (310 mg, 0.43 mmol) in 80% aqueous AcOH (4 mL) was stirred at room temperature for 2 hr. Mixture was concentrated under low pressure and by silica gel column (DCM / MeOH = 50/1 eluting) and the residue was purified by preparative HPLC to obtain a white solid of 224 (79mg, 50%). ESI-MS: m/z 464.0 [M+H] ⁺ .

Example 123

Prepared using the procedures analogous 223-2, isopropanol (21g, 350mmol) and POCl3 (53.6g, 350mmol) of a solution prepared 225-2. 225-2 (40.5 g, 65% yield) was obtained as a colorless liquid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 4.94 - 5.10 (m, 1H), 1.48 (d, J = 6.17 Hz, 6H); ³¹ P-NMR (162 MHz, CDCl ₃ ) δ=5.58 (br.s) ., 1P).

224-3 prepared using the analogous procedure using 225-2 (124mg, 0.7mmol) and 227-A (310mg, 0.5mmol) prepared 225-3. 225-3 (300 mg, 83%) was obtained as a solid.

Using a procedure similar to that of Preparation 224 , 225 was prepared using EtOAc ( EtOAc ) 225 (80 mg, 43%) was obtained as a white solid. ESI-MS: m/z 450.0 [M+H] ⁺ .

Example 124

Compound 227

1-Naphthol (1.88 g, 13 mmol) was added to a stirred solution of POCl ₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL), and TEA was added dropwise at -70 °C. (1.31 g, 13 mmol) in DCM (3 mL). The mixture was gradually warmed to room temperature and stirred for 1 hour. The crude product 227-1 was obtained.

At -70 ℃, the (S) -2- propionic acid isopropyl ester hydrochloride (2.17g, 13mmol) in the in DCM (10mL) was added a stirred solution of the crude product 227-1. TEA (2.63 g, 26 mmol) was added dropwise to the stirred solution at -70 °C. The mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and quenched with n-propylamine. The mixture was concentrated under reduced pressure, and the residue was purified by EtOAc ( EtOAc: EtOAc: EtOAc: EtOAc )

At 0 deg.] C, was added 227-2 (240mg, 0.674mol to 227-A (300mg, 0.337mmol) and NMI (276mg, 3.37mmol) in dry CH ₃ CN (4mL) in the solution in DCM (5mL) in). The mixture was stirred at room temperature for 10 hours. The reaction was monitored by LCMS. The reaction was quenched with water, and extracted with _{CH 2 Cl 2 (3 × 20mL} ). The organic phase was dried over anhydrous MgSO4 and evaporated. The residue was purified by EtOAc ( EtOAc: EtOAc = EtOAc ( EtOAc )

The 227-3 (380mg, 0.314mmol) was dissolved in _{CH 3 COOH (80%, 8mL} ), and stirred at 40-50 ℃ 2.5 hours. The reaction was monitored by LCMS. The mixture was concentrated low pressure, and by chromatography (PE: EA = 1: 1 to EA) to afford a crude product was obtained residue 227. By preparative HPLC (neutral systems, NH ₄ HCO ₃₎ purification of the crude product was obtained as a white solid of pure 227 (70mg, 80%). ESI-MS: m/z 665.1 [M+H] ⁺ .

Example 125

1-Naphthol (1.88 g, 13 mmol) was added to a stirred solution of POCl ₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL), and TEA was added dropwise at -70 °C. (1.31 g, 13 mmol) in DCM (3 mL). The mixture was gradually warmed to room temperature and stirred for 1 hour. A crude product solution of 227-1 was obtained.

At -70 ℃, the (S) -2- propionic acid in the isobutyl ester hydrochloride (2.35g, 13mmol) in DCM (20mL) under nitrogen was added TEA (2.63g, 26mmol) and 228 -1 crude product solution. The mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and quenched with n-propylamine. The solvent was evaporated under reduced pressure and the residue was purified ( jjjjjjjjjj

At 0 deg.] C, was added 228-2 (249mg, 0.674mol to 227-A (300mg, 0.337mmol) and NMI (276mg, 3.37mmol) in dry CH ₃ CN (4mL) in the solution in DCM (5mL) in). The mixture was stirred at room temperature for 10 hours. The reaction monitored by LCMS, and then quenched with ₂ O H. The mixture was extracted with _{CH 2 Cl 2 (3 × 20mL} ). The organic phase was dried over anhydrous MgSO4 and evaporated. The residue was purified by chromatography ( EtOAc: EtOAc = EtOAc = EtOAc :

The 228-3 (360mg, 0.294mmol) was dissolved in _{CH 3 COOH (80%, 8mL} ), and stirred at 40-50 ℃ 2.5 hours. The reaction was monitored by LCMS and then quenched with EtOAc. The mixture was concentrated low pressure, and by chromatography (using PE: EA = 1: 1 as eluent) to afford the crude product 228. By preparative HPLC (neutral systems, NH ₄ HCO ₃₎ was obtained as a purified product 228 (70mg, 75%) of a white solid. ESI-MS: m/z 679.2 [M+H] ⁺ .

Example 126

At -70 deg.] C, was added phenol (1.22g, 13mmol) was stirred in to the POCl ₃ (2.0g, 13mmol) in dry DCM (10mL) over a solution, and a solution containing TEA at -70 ℃ (1.31g , 13 mmol) of DCM (3 mL). The mixture was gradually warmed to room temperature and stirred for 1 hour. A crude product solution of 227-1 was obtained.

Using a procedure similar to that of Preparation 228 , 229-2 (205 mg, 0.674 mol, in DCM (5 mL), obtained from (S)-2- aminopropionate hydrochloride and 229-1 ) and 227 Preparation of 229 by -A (300 mg, 0.337 mmol). 229 (50 mg, 74%) was obtained as a white solid. ESI-MS: m/z 615.2 [M+H] ⁺ .

Example 127

Compound 230

228 was prepared using the analogous procedure using 230-2 (214mg, 0.674mol, in DCM (5mL) in, obtained from (S) -2- propionic acid isopropyl ester hydrochloride and 230-1) and 227 -A (300 mg, 0.337 mmol) was prepared in 230 . 230 (70 mg, 87%) was obtained as a white solid. ESI-MS: m/z 629.2 [M+H] ⁺ .

Example 128

Using a procedure similar to that of Preparation 228 , using 231-2 (223 mg, 0.674 mol, in DCM (5 mL), obtained from (S)-2- aminopropionate hydrochloride and 231-1 ) and 227 Preparation of 231 by -A (300 mg, 0.337 mmol). 231 (62 mg, 71%) was obtained as a white solid. ESI-MS: m/z 641.2 [M+H] ⁺ .

Example 129

Compound 232

228 was prepared using the analogous procedure using 232-2 (223mg, 0.674mol, DCM ( 5mL), was obtained from (S) -2- propionic acid and 3-pentyl ester hydrochloride 232-1) and 227- A (300 mg, 0.337 mmol) was prepared in 232 . 232 (42 mg, 60%) was obtained as a white solid. ESI-MS: m/z 643.2 [M+H] ⁺ .

Example 130

Treatment of phosphonium trichloride (1.00 g, 6.58 mmol) and 5-quinoline (955 mg, 6.58 mmol) in anhydrous DCM (50 mL) with EtOAc (EtOAc) The solution is stirred in the middle. The mixture was gradually warmed to room temperature and stirred for 2 hours. The solution was cooled to -78 ° C then treated with (S)-2-aminopropionic acid neopentyl ester hydrochloride (1.28 g, 6.58 mmol). TEA (1.33 g, 13.16 mmol) was added dropwise at -78 °C. The mixture was gradually warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in methyl-butyl ether. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc )

At 0 ℃, to 233-2 (300mg, 0.337mmol) and NMI (276.6mg, 3.37mmol) in dry CH ₃ CN (0.9mL) are added dropwise the solution containing 233-1 (388mg, 1.011mmol) CH ₃ CN (0.3 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with water and EtOAc evaporated. The organic phase was washed with brine, dried over anhydrous sodium The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc )

The 233-3 (300mg, 0.243mmol) was dissolved in _{80% CH 3 COOH (3mL)} , and the mixture was stirred at 60 deg.] C for 2.5 hours. The mixture was partitioned between AcOEt and water. The organic layer was washed with brine, dried over sodium sulfate and evaporated. By silica gel column (inclusive of PE 50% EA) to afford a yellow powder of 233 (81mg, crude product). The crude product was purified by RP HPLC (81 mg) was obtained as a white solid of 233. (28.7 mg, 17.1%). ESI-LCMS: m/z 694.1 [M+H] ⁺ .

Example 131

A procedure similar to that of Preparation 233-1 was used, using phosphonium trichloride (2.00 g, 13.16 mmol), 1-naphthol (1.882 g, 13.16 mmol), and ( S )-2-aminopropionic acid neopentyl HCl. Salt (2.549 g, 13.16 mmol) was prepared in 234-1 . Obtained 234-1 (600 mg, 12%) as a colorless oil.

At room temperature, 234-1 (300mg 0.78mmol) in dry CH ₃ CN (0.5mL) was treated in the 234-2 (230mg 0.26mmol) and NMI (212mg 2.60mmol) in dry CH ₃ CN (1mL) Solution in the middle. The mixture was stirred overnight at room temperature. The reaction was quenched with EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous sodium sulfate By silica gel column (CH ₃ OH containing the CH ₂ Cl _2, 1% to 5%) was obtained as the residue was purified 234-3 (300mg, 93%) of a white solid.

The 234-3 (300mg, 0.24mmol) was dissolved in _{CH 3 COOH (80%, 5mL} ). The mixture was stirred at 60 ° C for 2.5 hours. The mixture was diluted with EA (30 mL) and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. By silica gel column (CH ₃ OH containing the CH ₂ Cl _2, 1% to 5%) to obtain a crude product The residue was purified 234 (105mg). By HPLC (water containing 0.1% NH ₄ HCO ₃ and the CH ₃ CN) purification of the crude product was obtained as a white solid of 234 (45mg, 26%). ESI-LCMS: m/z 693.2 [M+H] ⁺ .

Example 132

The solution of 235-1 (2.00 g, 13.99 mmol) and 235-2 (2.00 g, 13.99 mmol) in anhydrous DCM was taken dropwise with a solution of TEA (3.11 g, 30.8 mmol) in DCM (20 mL). The stirred solution in 8 mL). The mixture was stirred at -78 °C for 2 hours, then gradually warmed to room temperature. The organic solvent was removed at low pressure and the residue was dissolved in methyl-butyl ether. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified on a EtOAc EtOAc ( EtOAc:EtOAc )

235-4 (260mg, 0.29mmol) was co-evaporated with toluene three times to remove the H ₂ O. Dry 235-4 was treated with MeCN (0.8 mL) and NMI (240 mg, 2.9 mmol) and then stirred for 10 min. The mixture was treated with a solution of 235-3 (291 mg, 0.87 mmol The residue was purified on EtOAc EtOAc ( EtOAc )

Processing 235-5 (300mg, 0.25mmol) with _{CH 3 COOH (5mL, 80%} ), and stirred at 50 ℃ 3 hours. The mixture was diluted with EA. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. By silica gel column chromatography (67% EA of containing PE) to obtain a crude product The residue was purified by 235, which was purified by HPLC. The product was dried to give 235 (30 mg, 18.5%) as a white solid. ESI-LCMS: m/z 643 [M+H] ⁺ .

Example 133

247-1 (50 mg, 0.13 mmol) was dissolved in 80% formic acid (3 mL) and warmed overnight at 50 °C. The solvent was evaporated and co-evaporated with water to remove the acid. The residue was dissolved in a mixture of methanol and triethylamine (3 mL, 4:1 v: v). After 0.5 hours, the solvent was evaporated. 247 (40 mg, 97%) was obtained from lyophilized nucleoside. MS: mz 315.5 [M-1].

Example 134

Compound 248

At 0 deg.] C, under N ₂ atmosphere, was added BzCl to 248-1 (15.0g, 50.2mmol) in anhydrous pyridine was (180 mL of) the stirred solution of (23.3g, 165.5mmol). The mixture was stirred at room temperature for 12 hours. The mixture was diluted with EA, and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The organic phase was concentrated to dryness under reduced pressure. By column chromatography (inclusive of PE 15% EtOAc) to afford the residue obtained was 248-2 (27g, 93.5%) of a white solid.

248-2 (27.0 g, 47 mmol) was dissolved in 90% HOAc (250 mL). The mixture was stirred at 110 ° C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with EA and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The organic phase was concentrated to a low pressure to obtain 248-3 (21.7g, crude product) as a light yellow solid of crude product.

Processing 248-3 (21.7g, 45.9mmol) with NH ₃ / MeOH (600mL), and stirred at room temperature for 12 hours. The solvent was concentrated under reduced pressure to give a crude material. The crude product was purified by EtOAc EtOAc EtOAc EtOAc

Isoimide (7.7 g, 113.6 mmol) and TBSCl (9.4 g, 62.5 mmol) were added to a stirred solution of 248-4 (15.0 g, 56.8 mmol) in anhydrous pyridine (200 mL). The mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with EA and washed with saturated aqueous NaHCO ₃ and brine. The organic phase was dried and filtered over anhydrous Na ₂ SO _4. The crude product was obtained as a pale yellow solid 248-5 (21.3 g, crude).

Trimethylpyridine (6.8 g, 56.8 mmol), MMTrCl (17.8 g, 56.8 mmol) was added to a stirred solution of 248-5 (21.3 g, EtOAc) AgNO ₃ (9.6 g, 56.8 mmol). The mixture was stirred at room temperature for 12 hours. The solid was removed by filtration, and saturated aqueous NaHCO ₃ and the filtrate was washed with brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc :

Compound 248-6 (32 g, 49.2 mmol) was dissolved in a solution of TBAF in THF (1M, 4.0 eq.). The mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with EA and washed with brine. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure (low procedure) and concentrated. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc :

Pyridine (9.2 mL, 116.4 mmol) and Dess-Martin periodinane (49 g, 116.4 mmol) were added to a stirred solution of 248-7 (21.0 g, 38.8 mmol) EtOAc. ). The mixture was stirred at room temperature for 4 hours. With Na ₂ S ₂ O ₃ saturated aqueous NaHCO ₃ solution and saturated reaction was quenched. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ dried and concentrated under reduced pressure to obtain a crude product (21.0g).

The crude product (21.0 g, EtOAc) was obtained eluted eluted eluted The mixture was stirred at room temperature for 12 hours. Solution was treated with NaBH ₄ (8.8g, 232.8mmol). After stirring at room temperature for 0.5 hours, the reaction was quenched with ice water. The mixture was diluted with EA and washed with brine. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography eluting with EtOAc EtOAc

248-8 (4.8 g, 8.5 mmol) was co-evaporated with toluene (2×). The residue was dissolved in anhydrous DCM (45 mL)EtOAcEtOAc The solution was cooled to 0 °C. Trifluoromethanesulfonic anhydride (4.8 g, 18.7 mmol) was added dropwise over 10 minutes. The mixture was stirred at 40 ° C for 40 minutes and was monitored by TLC (PE: EA = 1:1). The mixture was diluted with CH ₂ Cl ₂ (50mL). The solution was washed with a _saturated solution of NaHCO. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography ( EtOAc: EtOAc:EtOAc:EtOAc

248-9 (6.1 g, 7.3 mmol) was dissolved in MeCN (25 mL). A solution of TBAF in THF (1 M, 25 mL) was added at room temperature. The mixture was stirred at room temperature for 12 hours. A solution of TBAF in THF (1 M, 15 mL) was added and the mixture was stirred for 4 hr. The mixture was treated with aqueous NaOH (1N, 14.6 mmol) and mixture was stirred for 1 hour. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by column chromatography eluting with EtOAc EtOAc

248-10 (700 mg, 1.23 mmol) was dissolved in 80% HCOOH (40 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with MeOH (40 mL)EtOAc The solvent was concentrated low pressure, and by column chromatography (DCM 5% MeOH containing it) to afford a white solid was obtained of 248 (210mg, 57.7%). ESI-MS: m/z 296.9 [M+H] ⁺ .

Example 135

Compound 250

The 250-1 (120g, 0.26mol) and IBX (109g, 0.39mol) in a mixture of CH ₃ CN (2.0L) was heated to reflux and stirred for 12 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated to dryness at low pressure.

250-2 (130 g, crude product, 0.26 mol) was co-evaporated with anhydrous toluene (3×). Vinyl magnesium bromide (700 mL, 0.78 mol, 1.0 N in THF) was added dropwise to a solution of 250-2 in THF (300 mL) over 30 min at -78 ° C and the mixture was stirred at room temperature About 1 hour. When the starting material was consumed as judged by TLC, the mixture was poured into a saturated solution of NH ₄ Cl. The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure.

(, 0.346mol 170g, crude) in dry CH was added to the above residue in ₂ Cl ₂ solution of TEA (105g, 1.04mol), DMAP (84g, 0.69mol) and benzoyl chloride (146g, 1.04mol) And stirred at room temperature for 12 hours. The mixture _diluted with CH Cl ₂ and washed with saturated aqueous NaHCO _3. The combined aqueous phases were extracted with DCM (100 mL). The combined The organic phase was dried over anhydrous Na ₂ SO _4, filtered and evaporated to dryness under reduced pressure. The residue was purified by column chromatography using EA EtOAc (10% to 50%) to afford 250-3 (107 g, 52%).

The uracil (co-evaporated with toluene (2 ×)) NOBSA mixture of (81.4g, 0.4mol) and CH ₃ CN (150mL) was stirred to reflux for 1.5 hours. After cooling to room temperature, the mixture was treated with 250-3 (59 g, 0.1 mol) and TMSOTf (155 g, 0.7 mol). The mixture was heated to 60-70 ° C and stirred for 12 hours. After cooling to room temperature, the mixture was poured into a saturated NaHCO ₃ solution, and a solid precipitated. After filtration, pure 250-4 (40 g, 69%) was obtained as white solid.

Add PMBCl (16 g, 0.1 mol) to a solution of 250-4 (50 g, 0.086 mol), K ₂ CO ₃ (17.8 g, 0.13 mol) in DMF (50 mL) at EtOAc. Stir for 12 hours. The reaction was quenched with water and extracted with EtOAc EtOAc. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to a low pressure to obtain 250-5 (65g).

A mixture of 250-5 (65 g, 0.086 mol) and NaOMe (16.8 g, 0.3 mol) in MeOH: DCM (500 mL, v: v = 4:1) was stirred at room temperature for 2.5 hours. The reaction was quenched with CO ₂ (solid) and a low-pressure concentrated. The residue was dissolved in EA (200 mL). The solution was washed with water, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by column chromatography eluting with EtOAc EtOAc

NaH (10.5 g, 0.26 mol, 60% in kerosene), BnBr (36.3 g, 0.21 mol) and in the chamber were added to a mixture of 250-6 (25.5 g, 0.065 mol) in DMF (60 mL). Stir for 12 hours at room temperature. With NH ₄ Cl (aq) the reaction was quenched, and the mixture was diluted with EA (150mL). The solution was washed with brine, dried over anhydride Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by silica gel (15% EA PE) to afford 250-7 (20 g, 46%).

OsO ₄ (2.6 g, added to a solution of 250-7 (20 g, 0.03 mol) and NMMO (7 g, 0.06 mol) in THF:H ₂ O (100 mL, v:v=5:1) 0.01 mol) and stirred at room temperature for 24 hours. The reaction was quenched with ₂ S ₂ O ₃ saturated solution, Na, and extracted with EA (3 × 80mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure.

To a solution of the diol product (0.03 mol) in MeOH: H ₂ O: THF (v: v: v = 170 mL: 30mL: 50mL), NaIO ₄ (9.6 g, 0.045 mol) Stir at room temperature for 2 hours. After filtering, the filter is used directly in the next step.

The solution was treated with NaBH ₄ (1.8 g, 0.048 mol) at 0 ° C and stirred at room temperature for 30 min. The reaction was quenched with HCl (1N) solution. The mixture was extracted with EA (3 x 60 mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc ( EtOAc: EtOAc: EtOAc: EtOAc: EtOAc :

At 0 deg.] C, was added MsCl (3.1g, 27mmol) in the direction (14g, 21mmol) and DMAP (5.1g, 42mmol) in DCM (60mL) was 250-8 and stirred at room temperature for 40 minutes. With a saturated solution of NaHCO ₃ The reaction was quenched. The organic phase was washed with HCl (0.2N), dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified with EtOAc (EtOAc:EtOAc)

The Ms-product (41 g, 55 mmol) was treated with EtOAc (EtOAc, EtOAc (EtOAc) Concentrate the mixture at low pressure. The residue was dissolved in EA (200 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by a silica gel column (PE containing 25% EA) to afford 250-9 (9.9 g, 27%).

Add (1,52mL v:: v = 3 ) in a solution of CAN (15.5g, 28.3mmol), and stirred overnight at room temperature: to 250-9 (6.3g, 9.45mmol) in CAN H ₂ O. The reaction was quenched with water and extracted with EtOAc EtOAc. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography eluting with EtOAc EtOAc

At -70 ℃, (2.4g, 4.4mmol) in dry DCM (10mL) was added to a solution of the _{250-10 BCl 3 (1N, 30mL)} , and stirred at -70 ℃ 2 hours. The reaction was quenched with MeOH at -70 °C. The mixture was concentrated directly at 35 ° C under low pressure. The residue was purified by column chromatography ( EtOAc to 50% EtOAc to EtOAc ) ESI-MS: m/z 277.1 [M+H] ⁺ .

At 0 ℃, the PPh ₃ (3.37g, 12.8mmol) in pyridine (15mL) was added in the I ₂ (3.06g, 12mmol), and stirred at room temperature for 30 minutes until the orange presentation. The mixture was cooled to 0 deg.] C, and treated with pyridine (5mL) containing 250-11 (2.2g, 8mmol) of, and at room temperature, under N _2, stirred for 12 hours. The reaction was treated with Na ₂ S ₂ O ₃ (saturated, 30 mL) quenched and extracted with EA (3 × 60mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography eluting with EtOAc EtOAc

250-12 stirred at 60-70 ℃ (1.35g, 3.5mmol) and DBU (1.06g, 7mmol) in _{THF: CH 3 CN (v:} v = 10mL: 5mL) mixture of 2 hours. The mixture was diluted with EA (50 mL) and adjusted to pH = 7-8 using HCl (0.2N). The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography to afford 250-13 (0.5 g, 55%).

At 0 ℃, was added to the NIS in the ₃ CN (6mL) solution of 250-13 (670mg, 2.6mmol) in CH of (730mg, 3.25mmol) and 3HF. TEA (335 mg, 2.1 mmol) was stirred at room temperature for 2 h. The reaction was, and extracted with EA (3 × 30mL) with NaHCO ₃ (saturated) was added and Na ₂ S ₂ O ₃ (saturated) was quenched. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography eluting elut elut elut elut elut elut eluting

To a solution of 250-14 (1.0 g, 2.47 mmol), DMAP (0.75 g, 6.2 mmol) and TEA (0.75 g, 7.42 mmol) in DCM (10 mL) 8.16 mmol) of DCM (1 mL). With NaHCO ₃ (aqueous) was added The reaction was quenched. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography (30% EtOAc ) to afford 250-15 (850 mg, 85%).

A mixture of 250-15 (600 mg, 1 mmol), BzONa (1.45 g, 10 mmol) and 15-cr--5 (2.2 g, 10 mmol) in DMF (25 mL) was stirred at 90-100 °C for 24 hours. The mixture was diluted with EA (20 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography eluting with EtOAc (30% EtOAc )

Stirring 250-16 (250mg, 0.41mmol) in NH ₃ at room temperature. The mixture in MeOH (7N, 5 mL) was 15 min. The mixture was concentrated directly at low pressure. By column chromatography (50% EA contains the PE) and the residue was purified again by prep. HPLC to afford a white solid of 250 (33mg, 25%). ESI-MS: m/z 295.1 [M+H] ⁺ .

Example 136

Compound 126

At 25 ℃, under N ₂ atmosphere, to 126-1 (3.0g, 11.15mmol) in anhydrous pyridine (90 mL) was added a solution of the imidazole (3.03g, 44.59mmol) and TBSCl (6.69g, 44.59mmol) . The solution was stirred at 25 ° C for 15 hours. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EA. The solution was washed with saturated NaHCO ₃ and brine, and dried over anhydrous MgSO _4. The solvent was removed in vacuo to afford crude product 126-2 (4.49 g, 90%) as a white solid.

TsOH (10.7 g, 56.34 mmol) was added to a stirred solution of 126-2 (3.5 g, 7.04 mmol). The mixture was stirred at 30 ° C for 8 hours. Water (30 mL) was added and the solution was removed to dryness. The residue was purified on a EtOAc EtOAc EtOAc EtOAc .

At 25 ℃, under N _2, was added to 126-3 (3.4g, 8.88mmol) in dry pyridine (17mL) in a solution of trimethyl pyridine _{(4.3g, 35.51mmol), AgNO 3} (5.50 g, 35.51 mmol) and MMTrCl (8.02 g, 26.63 mmol). The mixture was stirred at 25 ° C for 12 hours. MeOH (20 mL) was added and the solvent was removed to dryness at low pressure. The residue was purified on a silica gel column ( EtOAc EtOAc EtOAc )

Cl is added to 126-4 (2.0g, 2.16mmol) (10mL ) in a solution of anhydrous DCM was added dropwise at _{-78 ℃ 2 CHCOOH (2.8g, 21.57mmol} ). The mixture was allowed to warm to -10 ° C and stirred at this temperature for 20 minutes. At -10 ℃ ₃ The reaction was quenched with saturated NaHCO. The mixture was extracted with DCM, washed with brine, and dried over anhydrous MgSO _4. Low pressure concentrated solution. The residue was purified on a silica gel column ( EtOAc EtOAc EtOAc )

DCC (3.30 g, 16.03 mmol) and Py. were added to a stirred solution of 126-5 (3.5 g, 5.34 mmol) in anhydrous DMSO (35 mL). TFA (1.03 g, 5.34 mmol). The mixture was stirred at 30 ° C for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. The precipitate was filtered. The organic layer was washed with brine (3 ×) was washed and dried over anhydrous MgSO _4. The organic phase was concentrated under reduced pressure to afford crude material 126-6 (3.5 g).

To a stirred solution of 126-6 (3.5 g, 5.34 mmol) in MeCN (35 mL), 37% <RTI ID=0.0></RTI></RTI><RTIgt; The mixture was stirred at 25 ° C for 12 hours. And NaBH ₄ (3.25g, 85.5mmol) the mixture was treated with EtOH (26mL), followed by stirring for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EA (3 × 60mL). The organic layer was dried over anhydrous MgSO _4, and concentrated under low pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc

At -35 deg.] C, under N ₂ atmosphere, and the in DCM (9.6 mL) was added DMTrCl stirred in pyridine (24 mL of) to 126-7 (1.85g, 2.7mmol) (1.3g , 3.9mmol). The solution was stirred at 25 ° C for 16 hours. The mixture was treated with MeOH (15 mL) and concentrated. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc

Adding AgNO to 126-8 (1.07g, 1.08mmol) in dry pyridine (5mL) in a solution of ₃ (0.65g, _3.79mmol) and TBDPSCl (1.04g, 3.79mmol). The mixture was stirred at 25 ° C for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in EA (50 mL). The resulting solution was washed with brine. The organic layer was dried over anhydrous MgSO _4, and concentrated under low pressure. The residue was purified on a silica gel column ( EtOAc EtOAc EtOAc )

At -78 ℃, to 126-9 (1g, 0.82mmol) was added Cl ₂ CHCOOH (2.69mL) in dry DCM (13.43mL) in the stirred solution. The mixture was stirred at -10 ° C for 20 minutes. With saturated aqueous NaHCO ₃ The reaction was quenched and extracted with DCM. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The organic phase was purified by column chromatography ( EtOAc EtOAc EtOAc EtOAc

Pyridine (171 mg, 2.17 mmol) and Tf ₂ O (183 mg, 0.65 mmol) were added dropwise to ice-cooled solution of 126-10 (0.4 g, 0.433 mmol). The mixture was stirred at -10 ° C for 20 minutes. The reaction was quenched with ice water and stirred for 30 min. The mixture was extracted with DCM (3×20 mL). The organic phase was washed with brine (100mL), dried over anhydrous Na ₂ SO ₄ dried and concentrated to a low pressure to obtain a crude product 126-11 (0.46g), which was used without further purification in the next step.

To 126-11 (0.46g, 0.43mmol) in dry DMF (2.5mL) was added in the NaN ₃ (42mg, 0.65mmol). The mixture was stirred at 30 ° C for 16 hours. The solution was diluted with water and extracted with EA (3×30 mL). The dried Na ₂ SO ₄ the combined organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified on a silica gel column ( EtOAc EtOAc EtOAc EtOAc EtOAc

At 70 ℃, to 126-12 (0.31g, 0.33mmol) in MeOH was added (5mL) in a solution of _{NH 4 F (0.36g, 9.81mmol)} . The mixture was stirred at this temperature for 24 hours. The mixture was evaporated to dryness. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc:EtOAc

126-13 (300 mg, 0.50 mmol) was dissolved in 80% HOAc (20 mL). The mixture was stirred at 55 ° C for 1 hour. The reaction was quenched with MeOH and concentrated EtOAc. The residue was purified by preparative EtOAc (EtOAc) ESI-LCMS: m/z 325.1 [M+H] ⁺ .

Example 137

At 0 deg.] C (ice / water bath) to 146-1 (80mg, 0.14mmol) in dry CH of the ₃ CN (2.0mL) was added a stirred solution of N- methylimidazole (0.092mL, 1.12mmol). Followed by (isopropoxy -L- alanine-yl) phenyl phosphate chloride solution (128mg, 0.42mmol, was dissolved in CH ₃ CN (0.5mL) in) (as according to McGuigan et al., J.Med.Chem. (2008) 51: 5807-5812 prepared by the general procedure). The solution was stirred at 0 to 5 ° C for an hour, followed by stirring at room temperature for 16 hours. The mixture was cooled to 0 to 5 ° C, diluted with EA then water (5 mL). Solution, NaHCO ₃ and washed with 1.0M aqueous citric acid and saturated brine, and dried over MgSO _4. In Silica (10g column with EA / hexanes (25-100% gradient)) obtained residue was purified on a foamy of 137-1 (57.3mg, 49%).

The 137-1 (57.3mg, 0.07mmol) was dissolved in ₃ CN (0.5mL) in dry CH, and was added in dioxane (68μL, 0.27mmol) 4N HCl at 0 to the 5 ℃. The mixture was stirred at room temperature for 2 hours, and anhydrous EtOH (100 μL) was added. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). In Silica (10g column, with a gradient of 1-7% _{MeOH / CH 2 Cl 2 ()} ) and the residue was purified lyophilized to obtain a white foam of 137 (27.8mg, 72%). ESI-LCMS: m / z = 571.1 [M + H] +, 1141.2 [2M + H] +.

Example 138

In the same manner as the 169-4 from 146-1 (100mg, 0.174mmol) and bis (tert-butoxy carbonyl methyl group) phosphate (126mg, 0.35mmol) containing DIPEA (192μL, 1.04mmol) 138-1 (68.4 mg, 44.7%) was prepared from THF (1.5 mL) of EtOAc (EtOAc)

In the same manner as in the 146, since 138-1 (68mg, 0.077mmol) Preparation 138 (31.4mg, 67%). ESI-LCMS: m / z = 627.15 [M + Na] +, 1219.25 [2M + H] +.

Example 139

To 146-1 (100mg, 0.175mmol) in dry CH of the ₃ CN (2mL) -1H- tetrazole was added a solution of 5-ethylthio-of CH _{3 CN (0.25M; 0.84mL, 0.21mmol} ). CH ₃ CN (1 mL) containing bis-SATE-amino phosphate (95 mg, 0.21 mmol) was added dropwise at 0 to 5 °C. The mixture was stirred at 0 to 5 ° C for 2 hours under Ar. A solution of 77% m- CPBA (78 mg, 0.35 mmol) in DCM (1 mL) elute. The mixture was diluted with EtOAc (50mL), with 1.0M citric acid, washed with saturated NaHCO ₃ and brine, and dried over MgSO _4. The mixture was filtered and the solvent was evaporated in vacuo. In Silica (10g column with EA / hexanes (20-100% gradient)) obtained residue was purified on a white foam of 139-1 (105mg, 63.6%).

The 139-1 (105mg, 0.112mmol) was dissolved in anhydrous CH ₃ CN (0.8mL), was added and 4N HCl in dioxane of (84μL, 0.334mmol) at 0 to 5 ℃. The mixture was stirred at room temperature for 2 hours. Anhydrous EtOH (100 μL) was added. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). In Silica (10g column, with a gradient of 1-7% _{MeOH / CH 2 Cl 2 ()} ) and the residue was purified lyophilized to obtain a white foam of 139 (42.7mg, 57%). ESI-LCMS: m / z = 692.15 [M + Na] +, 1339.30 [2M + H] +.

Example 140

BB (250.00 mg, 285.73 μmol) was added to a solution of N-Boc-L-proline acid (620.78 mg, 2.86 mmol) and TEA (144.57 mg, 1.43 mmol) in anhydrous THF (2.5 mL). The mixture was co-evaporated with pyridine and toluene to remove water. The residue was dissolved in THF (2.5 mL). DIPEA (369.28 mg, 2.86 mmol) was added at room temperature (18 ° C) followed by BOP-Cl (363.68 mg, 1.43 mmol) and 3-nitro-1H-1,2,4-triazole (162.95 mg) , 1.43mmol). The mixture was stirred at room temperature for 12 hours then diluted with EA (40 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, concentrated to dryness and a low pressure. The residue was purified on a EtOAc EtOAc EtOAc (EtOAc)

143-1 (250.0 mg, 232.73 μmol) was dissolved in 80% CH ₃ COOH (30 mL). The solution was heated to 50 ° C and stirred for 12 hours. The reaction was quenched with MeOH and the solution was concentrated to dry. On silica gel column (5% MeOH in the DCM) is obtained residue was purified white foam of 143-2 (80.00mg, 68.82%).

143-2 (78.00 mg, 156.16 μmol) was dissolved in HCl / dioxane (1.5 mL) and EA (1.5 mL) at room temperature (19 ° C). The mixture was stirred at room temperature for 30 minutes. The solution was concentrated to dryness at low pressure. The residue was purified by preparative HPLC was obtained as a white solid of 143 (23mg, 31.25%). ESI-MS: m/z 400.20 [M+H] ⁺ , 799.36 [2M+H] ⁺ .

Example 141

154-1 was prepared according to the procedure described in Lefebre et al. J. Med. Chem. (1995) 38: 3941-3950, which is incorporated herein by reference for its limited purpose for the description of preparation 154-1 . in.

154-2 (0.33 g, 0.5 mmol) was prepared using a procedure similar to that used 155-5 and 154-1 . 154-2 was obtained as a white solid. The preparation 155 using a similar procedure, by preparative ^{154-2 154 (130mg) 1 H-} NMR (CDCl 3): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t , 2H), 4.1-4.2 (m, 6H), 3.2 (t, 4H), 1.69 (s, 4H), 1.3 (s, 3H), 1.23 (s, 18H); ³¹ P-NMR (CDCl ₃ ): -2.4ppm.

Example 142

To a solution of sodium thiosulfate (4.26 g, 76.0 mmol) in EtOH (100 mL), EtOAc (EtOAc (EtOAc) . A solution of 2-(2-chloroethoxy)ethanol (57 mmol; 6.0 mL) and EtOAc (EtOAc m. The mixture was filtered and concentrated to a small volume. The residue was dissolved in EA, and then washed with water, saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product (10.0 g) was purified eluting elut elut elut eluting ¹ H-NMR (CDCl ₃ ): 3.70-3.74 (m, 2H), 3.5-3.65 (m, 4H), 3.1 (t, 2H), 1.25 (s, 9H).

To a stirred solution of N,N-diisopropyldichlorophosphate (2.0 mL, 10.9 mmol) in THF (50 mL) was added 155- 3 (4.5 g; 21.8 mmol) and a solution of triethylamine (6.7 mL, 87.2 mmol) in tetrahydrofuran (50 mL). The mixture was stirred at room temperature for 2 hours then diluted with EA (200 mL). The mixture was washed with a saturated aqueous solution of NaCl and dried over Na ₂ SO ₄ . After filtration, the filtrate was evaporated <RTI ID=0.0> By flash column chromatography (containing EA (0-5%) containing 5% of triethylamine in hexanes, gradient) to afford a clear colorless oil of 155-4 (2.5g, 4.25mmol). _{^{1 H-NMR (CDCl 3)}} : 3.70-3.82 (m, 4H), 3.57-3.65 (m, 10H), 3.1 (t, 4H), 1.25 (s, 18H), 1.17 (t, 12H); 31 P -NMR (CDCl ₃ ): 148.0 ppm.

155-5 (285 mg, 0.9 mmol) and DCI (175 mg, 1.5 mmol) were co-evaporated twice with ACN and then dissolved in ACN (5 mL). Add 155-4 (790 mg, 1.35 mmol) of ACN (4 mL) and the reaction was monitored by TLC. After 15 minutes, a third butyl hydroperoxide (0.5 mL, 5.5 M solution in decane) was added and the mixture was stirred for 10 min. The mixture was diluted with EA (25mL), washed with saturated aqueous NaHCO ₃ and saturated aqueous NaCl, dried over Na ₂ SO _4, filtered and concentrated. Purification by flash column chromatography ( EtOAc EtOAc ( EtOAc ) 155-6 was dissolved in 80% aqueous HCOOH (5 mL). After 30 minutes at room temperature, the solvent was removed and co-evaporated twice with toluene. The residue was dissolved in MeOH (10 mL) and EtOAc (EtOAc) After 2 minutes at room temperature, the solvent was removed in vacuo. By flash column chromatography (containing methanol (0-15%) of DCM gradient) to afford 155 (90mg). ¹ H-NMR (CDCl ₃ ): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 3.70-3.82 ( m, 4H), 3.57-3.65 (m, 4H), 3.1 (t, 4H) 1.61 (s, 8H), 1.3 (s, 3H), 1.23 (s, 18H). ³¹ P-NMR (CDCl ₃ ): -1.55 ppm.

Example 143

Compound 156

Preparation of 156-1 (6.0 g, 31.6 mmol) was carried out using a procedure similar to the preparation of 155-3 using 4-chlorobutanol. Obtained 156-1 in a clear, colorless oil. ¹ H-NMR (CDCl ₃ ): 3.67 (s, 2H), 2.86 (m, 2H), 1.65 (m, 4H), 1.25 (s, 9H).

156-2 (2.14 g, 4.0 mmol) was prepared using a procedure similar to that used for the preparation of 155-4 . Obtained 156-2 in a clear, colorless oil. ¹ H-NMR (CDCl ₃ ): 3.67 (m, 6H), 2.86 (t, 4H), 1.65 (m, 8H), 1.25 (s, 18H), 1.17 (t, 12H). ³¹ P-NMR (CDCl ₃ ): 143.7 ppm.

156-3 (0.23 g, 0.22 mmol) was prepared using a procedure similar to the preparation of 155-6 using 155-5 and 156-2 . 156-3 was obtained as a white solid. 156 (170 mg) was prepared from 156-3 using a procedure similar to that of Preparation 155 . ¹ H-NMR (CDCl ₃ ): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 2.8 (t, 4H), 1.78 (m, 4H), 1.69 (s, 8H), 1.3 (s, 3H), 1.23 (s, 18H). ³¹ P-NMR (CDCl ₃ ): -1.56 ppm.

Example 144

161-1 (109 mg, 0.39 mmol) and bis(isopropoxycarbonyloxymethyl)triethylammonium phosphate (0.6 mmol, from 195 mg of bis(isopropoxycarbonyl) by co-evaporation with pyridine and toluene. (oxymethyl) phosphate and 85 μL of Et ₃ N prepared) anhydrous. The residue was dissolved in dry THF (3 mL) andEtOAc. Add diisopropylethylamine (0.2 mL, 3 equivalents), BopCl (190 mg, 2 eq.) and 3-nitro-1,2,4-triazole (81 mg, 2 eq.), and stir the mixture at 0 °C 90 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ and brine, and dried (Na ₂ SO _4). Purification on a silica gel column (with CH ₂ Cl ₂ /i-PrOH (4-10% gradient)) followed by RP HPLC purification (A: water with 0.1% HCOOH, B: MeCN with 0.1% HCOOH) yielded 161 (28 mg, 12%). ¹ H-NMR (CDCl ₃ ): δ 7.24 (d, 1H), 6.6 (br, 1H), 5.84 (d, 1H), 5.65-5.73 (m, 4H), 4.94 (m, 2H), 4.38 (m) , 2H), 4.1 (b, 1H), 2.88 (d, 1H), 1.47 (d, 3H), 1.33 (m, 12H).

Example 145

Compound 157-1 was prepared from commercially available 3-hydroxyoxetane (5.0 g) using the procedure described for Preparation 54-2 (5.6 g). ¹ H-NMR (CDCl ₃ ) δ 5.73 (s, 2H), 5.48-5.51 (m, 1H), 4.90 (d, 2H), 4.72 (d, 2H).

Compound 157-2 was prepared from 157-1 using the procedure described for Preparation 54-3 (8.0 g). ¹ H-NMR (CDCl ₃ ) δ 5.95 (s, 2H), 5.48-5.51 (m, 1H), 4.90 (d, 2H), 4.72 (d, 2H).

The benzyl phosphate (silver salt) was reacted with 157-2 (8.0 g) as described in Preparation 54-4 to give purified 157-3 (1.92 g). ¹ H-NMR (CD ₃ CN): δ 7.39-7.42 (m, 5H), 5.62 (d, 4H), 5.39-5.42 (m, 2H), 5.15 (d, 2H), 4.80-4.83 (m, 4H) ), 4.56-4.60 (m, 4H). ³¹ P-NMR (CD ₃ CN): δ -4.55 ppm.

Compound 157-3 (970 mg, 2.16 mmol) was dissolved in methanol (0.3 mL, 2.16 mmol) containing triethylamine. After 3 hours at room temperature, the solvent was evaporated in vacuo to afford crude material 157 -

Compound 157-5 (400 mg; 1.2 mmol) and 157-4 (900 mg, 2.16 mmol; 1.5×) were co-evaporated with pyridine (2×) and toluene (2×), then dissolved in THF (8 mL) at 0 ° C in. Diisopropylethylamine (DIPEA) (0.82 mL; 4 equivalents), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (Bop-Cl) (0.6 g; 2 equivalents), Nitrotriazole (0.266 g, 2 equivalents). The mixture was kept at 0 °C for 2 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc) The organic solvent was removed in vacuo. By flash chromatography (using a gradient of EA in hexanes 10-100%) was obtained residue was purified by purified 157-6 (175mg, 0.6mmol).

Purified 157-6 was dissolved in 80% aqueous HCOOH (20 mL) and kept at 20 °C for 1 hour. After cooling to room temperature, the solvent was removed in vacuo and the residue was evaporated with &lt;t&gt; toluene (3 x 25 mL). By flash chromatography (using DCM to 20% MeOH 0 of the gradient) the residue obtained was purified purified 157 (26mg). ESI-LCMS: m / z 589.6 [MH] -.

Example 146

Compound 158

Nucleoside 157-1 (from Wuxi) (44 mg, 0.15 mmol) was dissolved in a mixture of trimethyl phosphate (2 mL) and anhydrous pyridine (0.5 mL). The mixture was evaporated under vacuum at 42 °C for 15 minutes and then cooled to room temperature. N-methylimidazole (0.027 mL, 0.33 mmol) and POCl ₃ (0.027 mL, 0.3 mmol) were added sequentially. The mixture was kept at room temperature. The reaction was monitored by LC/MS with a 0-50% gradient. After 4 hours, the reaction was completed. The reaction was quenched with 2M aqueous triethyl ammonium acetate (2 mL), pH 7.5 (TEAA). A gradient of 158-2 was isolated on preparative HPLC (Phenomenex Synergi 4u Hydro-RP 250 x 21.2 mm) using a gradient of 0-30% ACN in 50 mM TEAA .

Compound 158-2 (triethylammonium salt; 45 mg, 0.1 mmol) was dried by repeated co-evaporation with anhydrous pyridine (3x). 158-2 was dissolved in anhydrous pyridine (1 mL) and the solution was added dropwise to a boiling solution of diisopropylcarbodiimide (63 mg, 0.5 mmol) in pyridine (4 mL). The mixture was heated under reflux for 1 hour. After cooling to 25 °C, the reaction was quenched with 2M EtOAc (2 mL) and kept at 25 ° C for one hour. The solution was concentrated to dryness and the residual pyridine was removed by co-evaporation with toluene (3 x 2 mL). A 158-3 was isolated on a preparative HPLC (Phenomenex Synergi 4u Hydro-RP 250 x 21.2 mm) using a gradient of 0-30% ACN in 50 mM TEAA .

Compound 158-3 (triethylammonium salt; 26 mg, 0.045 mmol) was dissolved in anhydrous DMF (0.5 mL). N,N-Diisopropylethylamine (40 μL, 0.22 mmol) and chloromethyl isopropyl ester (35 mg, 0.22 mmol) were sequentially added to the stirred solution. The mixture was stirred at 65 ° C for 18 hours. The mixture was evaporated to dryness, and the Silica column by using a gradient of 0-15% MeOH CH ₂ Cl ₂ Purification of the residue. Having convergence fractions were 158, and the mixture was concentrated to dryness to obtain 158 (2.3mg). ESI-LCMS: m/z 467.5 [MH] ^- .

Example 147

Add TsOH to a solution of 1,1-dimethoxycyclopentane (19.3 g, 148.52 mmol) and 221-1 (10.0 g, 37.13 mmol) in DCE (100 mL). H ₂ O (0.7 g, 3.71 mmol). The mixture was stirred at 50 ° C for 12 hours. The mixture was neutralized with Et ₃ N and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

Compound 221-2 (20.0g, 0.06mol) in dry pyridine and co-evaporated with three times to remove the H ₂ O. TsCl (22.8 g, 0.12 mol) was added to an ice-cooled solution of 221-2 in anhydrous pyridine (100 mL), and the mixture was stirred overnight. The reaction was monitored by LCMS and TLC. With H ₂ O The reaction was quenched, and the mixture was extracted with EA (3 × 200mL). The solution was dried over anhydrous Na ₂ SO ₄ and evaporation under low pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc

NaI (31.0 g, 0.2 mol) was added to a solution of 221-3 (20.0 g, 0.04 mol. The reaction was monitored by LCMS. The reaction was quenched with a saturated Na ₂ S ₂ O ₃ solution. The solution was extracted with EA (3 x 200 mL). Na ₂ SO ₄ organic layers were dried over anhydrous, and low pressure evaporator. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc :

Containing HCOOH (80%) of H ₂ O at room temperature treating compound 221-4 (13.4g, 30.16mmol). The solution was stirred at 60 ° C for 2 hours. Concentrate the mixture at low pressure. The residue was purified by EtOAc EtOAcjjjjjjj

At room temperature to 221-5 (5.0g, 13.22mmol) in anhydrous _{CH 3 CN / THF (50mL,} 1: 1, v: v) was added in the DBU (6.0g, 39.66mmol). The solution was stirred at 50 ° C for 1.5 hours. The reaction was quenched with HCOOH at 0 ° C then concentrated at low pressure. The residue was purified by column chromatography eluting elut elut elut elut eluting

Under N _2, to 221-6 (2.1g, 8.39mmol) in anhydrous MeCN was added NIS (2.4g, 10.49mmol) and TEA˙3HF (1.0g, 6.29mmol) (21mL ) in the ice cold solution. The mixture was stirred at room temperature for 1 hour. The reaction was, and extracted with EA (3 × 100mL) washed with saturated NaHCO ₃ and ₂ SO ₃ solution was quenched with saturated Na. The organic phase was dried over anhydrous Na ₂ SO _4, evaporated to dryness and a low pressure. The residue was purified on EtOAc EtOAc ( EtOAc:EtOAc :

DMAP (2.5 g, 20.20 mmol) and Et3N (2.5 g, 24.24 mmol) were added to a stirred solution of 221-7 (3.2 g, 8.08 mmol) EtOAc. The mixture was treated with BzCl (3.7 g, 26.66 mmol), then stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc EtOAc. The organic phase was concentrated under reduced pressure and EtOAc EtOAc ( EtOAc )

Bu ₄ NOH (8.0 g, 13.74 mL, 55% in H ₂ O) was adjusted to pH = 3-4 using TFA, then cooled to room temperature. At room temperature, a solution of Bu ₄ NOH and m -CPBA to in the 221-8 (600mg, 0.85mmol) in DCM (10mL) solution of (917mg, 4.25mmol, 80%) . The mixture was stirred at 25 ° C for 48 hours, followed by washing with a saturated NaHCO ₃ solution. The organic layer was passed directly through a basic Al ₂ O ₃ column and the solvent was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc :

Under N _2, to 221-9 (300mg, 0.50mmol) in EA / Hexane was added Lindlar catalyst (20mL, 1: v: 1 , v) in the solution (Lindlar catalyst) (200mg). The mixture was stirred at H ₂ (40 psi) for 1.5 hours at 2 °C. The suspension was filtered, and the filtrate was treated with a lindane catalyst (200 mg) under N ₂ and stirred at H ₂ (40 s) for 1.5 hrs. The mixture was filtered, and the filtrate was evaporated, mjjjjjjjj

Compound 221-10 (287mg, 0.48mmol) was dissolved in NH ₃ / MeOH in (30mL, 7M). The mixture was stirred at room temperature under N ₂ for 24 hours and then concentrated under reduced pressure. The residue was purified by preparative EtOAc ( EtOAc:EtOAc : ¹ H-NMR (CD ₃ OD, 400 MHz) δ = 7.86 (d, J = 8.0 Hz 1H), 6.26 (s, 1H), 5.62-5.86 (m, 1H), 5.49 (d, J = 17.1 Hz, 1 H), 5.30 (d, J = 10.5 Hz, 1H), 4.41 (d, J = 19.3 Hz, 1 H), 3.71-3.86 (m, 1H).

Compound 221-11 (113mg, 0.39mmol) was co-evaporated with toluene three times to remove the H ₂ O. Add 73-C (256 mg, 0.66 mmol) to MeCN to a stirred solution of 221-11 (113 mg, 0.39 mmol) in a mixture of MeCN (0.5 mL) and NMI (320 mg, 3.90 mmol). Solution in (0.5 mL). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. On silica gel column (5% MeOH in the DCM) to obtain the crude product The residue was purified 221 by preparative HPLC (water containing 0.1% HCOOH and MeCN) to afford a white solid of 221 (45mg, 20.1% ). ESI-MS: m/z </RTI><RTIID=0.0>^< / ^RTI>

Example 148

Under N _2, was added a wetting Pd / C (300mg, 10% ) to 221-9 (300mg, 0.50mmol) in the in MeOH (30mL) solution. The mixture was stirred at 25 ° C for 1.5 hours under H ₂ (1 atm). The suspension was filtered, then EtOAc ( EtOAc:EtOAc )

Compound 222-1 (307mg, 0.48mmol) was dissolved in NH ₃ / MeOH in (30mL, 7M). The mixture was stirred at room temperature under N ₂ for 24 hours and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc )

Compound 222-2 (91mg, 0.31mmol) was co-evaporated with toluene three times to remove the H ₂ O. At 0 ℃, to 222-2 (91mg, 0.31mmol) in a mixture of MeCN (0.5 mL) and NMI (254mg, 3.90mmol) of in the stirred solution was added 222-C (203mg, 0.66mmol) in MeCN ( Solution in 0.5 mL). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. On silica gel column (5% MeOH in the DCM) to obtain the crude product The residue was purified 222 by preparative HPLC (water containing 0.1% HCOOH and MeCN) to afford a white solid of 222 (30mg, 17% ). ESI-MS: m/z 540.1 [MF] ⁺ .

Example 149

TIPDSCl ( 70.78 g, 225.4 mmol) was added dropwise to an ice-cold solution of 226-1 (50 g, 204.9 mmol) in anhydrous Pd (400 mL). The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. 226-2 (111.5 g, 100%) was obtained as a white solid.

To 226-2 (50g, 103mmol) in dry was added a solution of IBX in _{CH 3 CN (400mL) (43g} , 153mmol) at room temperature. The mixture was refluxed overnight and was monitored by TLC (PE: EA = 1:1). The precipitate was filtered, and the title compound was crystaljjjjjjjjjj

At -78 ℃, alkyl trimethyl silicon to acetylene (20g, 200mmol) in dry THF (400mL) are added dropwise a solution of n -BuLi (80mL, 200mL). The mixture was stirred at -78 ° C for 30 minutes and then warmed to room temperature for 10 minutes. Compound 226-3 (30 g, 60 mmol) in THF (100 mL) was added dropwise at -78 °C. The mixture was stirred at -78 ° C for 1 hour, then slowly warmed to room temperature. The mixture was stirred for 20 minutes at -78 deg.] C and then with saturated NH ₄ Cl solution, the reaction was quenched. The mixture was diluted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

Under N ₂ Compound 226-4 (14g, 24mmol) was dissolved in dry toluene (100 mL) and cooled to -78 ℃. DAST (19 g, 120 mmol) was added dropwise at -78 °C and stirring was continued for 1.5 h. The mixture was diluted with EA and was poured into saturated NaHCO ₃ solution. The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

The mixture of 226-5 (12g, 20mmol) and NH ₄ F (11g, 30mmol) in MeOH (150mL) was refluxed for 2 hours. After chilling to rt, EtOAc ( EtOAc:EtOAc )

To a solution of 226-6 (3.1 g, 11.6 mmol) in EtOAc (EtOAc) The mixture was stirred at 50-60 ° C for 3 hours. The mixture was concentrated at low pressure and the residue was dissolved in EA (100 mL). The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

Add CuBr (643 mg, 4.5 mmol), dicyclohexylamine (3.3 g, 18 mmol) and trioxane (675 mg) to a solution of 226-7 (4.5 g, 9 mmol) in 1,4-dioxane (45 mL). , 22.5mmol). The mixture was refluxed for 24 hours and then cooled to room temperature. With saturated NH ₄ Cl solution, the reaction was quenched. The mixture was extracted with EA (3 x 100 mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

So 226-8 (2g, 4mmol) and NH ₄ F (2.2g, 60mmol) mixture (20mL) was refluxed overnight in the in MeOH. After chilling to rt, EtOAc (EtOAc: EtOAc)

At 0 ℃, to 226-9 (946mg, 3.33mmol), PPh 3 (1.3g, 5mmol), in the imidazole (453mg, 6.66mmol) and pyridine (3mL) in dry THF (12mL) stirred suspension of the in THF (4mL) was added dropwise I ₂ (1g, 4.33mmol). The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with EA (3 × 60mL). The organic layer was dried over Na ₂ SO _4, and concentrated under low pressure. The residue was purified with EtOAc EtOAc EtOAc .

To a solution of 226-10 (2.1 g, 5.3 mmol) in THF (15 mL) The mixture was diluted with EA and neutralized with acetic acid. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. By silica gel column chromatography (1.5% MeOH containing it in DCM) was obtained as a white residue of solid 226-11 (800mg, 90%).

Was added NEt ₃ ˙3HF to in the 226-11 (800mg, 3mmol) in dry MeCN (1.5mL) ice cold solution of (484mg, 3mmol) and NIS (1.68g, 7.5mmol). The mixture was stirred at room temperature for 30 minutes and the reaction was monitored by LCMS. The reaction was, and extracted with EA (3 × 50mL) with saturated Na ₂ S ₂ O ₃ and saturated NaHCO ₃ solution was quenched. Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc ( EtOAc )

To a solution of 226-12 (850 mg, 2 mmol) in dry EtOAc EtOAc (EtOAc) The mixture was stirred at room temperature for 4-5 hours and the reaction was monitored by LCMS. The mixture was diluted with CH ₂ Cl ₂ (40mL), and washed with saturated NaHCO ₃ solution. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The filtrate was evaporated under reduced pressure and EtOAc EtOAc ( EtOAc )

Tetrabutylammonium hydroxide (21 mL, 54-56% in water, about 42 mmol, 24 eq.) was adjusted to pH about 4 (ca. 3.5 mL) using TFA , and 226-13 (900 mg, 1.7 mmol) in DCM (21 mL) Solution solution in solution. The m-chloroperbenzoic acid (2.1 g, 60-70%, about 8.75 mmol, about 5 equivalents) was added portionwise with vigorous stirring, and the mixture was stirred overnight. The mixture was diluted with CH ₂ Cl ₂ (30mL), and washed with saturated NaHCO ₃ solution. The organic layer was washed with brine, dried over anhydrous magnesium The residue was purified by column chromatography ( EtOAc 40-EtOAc EtOAc) The residue was purified by TLC ( EtOAc EtOAc EtOAc )

(15mL) treating compound 226-14 (350mg, 0.86mg) 7N NH ₃ in MeOH with the. The mixture was stirred for 2-3 hours and monitored by TLC. The mixture was concentrated under reduced pressure and purified EtOAc EtOAc EtOAcjjjjj ¹ H NMR (CD ₃ OD, 400 M Hz) δ = 7.75 (d, J = 7.9 Hz, 1H), 6.60-6.35 (m, 1H), 5.72 (d, J = 8.2 Hz, 1H), 5.37-5.25 ( m, 1H), 5.17-5.06 (m, 1H), 5.04-4.94 (m, 1H), 4.59-4.29 (m, 1H), 3.87-3.70 (m, 2H).

To a solution of 226-16 (3.79 g, 18 mmol) and 226-17 (3 g, 18 mmol) in dry DCM (60 mL), EtOAc (4 g, 39 mmol) The solution was stirred and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in methyl-butyl ether. The precipitate was removed by filtration, and the filtrate was concentrated to give a crude material. The residue was purified by EtOAc EtOAc EtOAc .

Compound 226-15 (200mg, 0.66mmol) was co-evaporated with toluene three times to remove the H ₂ O. Compound 226-15 was treated with MeCN (1.5 mL) and NMI (541 mg, 6.6 mmol). The mixture was stirred at rt then EtOAc EtOAc ( EtOAc &lt By silica gel column (with 5% iPrOH of DCM) to obtain the crude residue was purified product which by HPLC (water containing 0.1% HCOOH and MeCN) to afford 226 (33mg, 9%). ESI-LCMS: m/z 594 [M+Na] ⁺ .

Example 150

Compounds 265 and 266

A solution of 266-1 (100 g, 384.20 mmol, 1.00 equiv) in N,N-dimethylformamide (1000 mL) was placed in a 2000 mL round bottom flask at room temperature. NaH (11.8 g, 491.67 mmol, 1.20 eq.) was added in several portions and the mixture was stirred at 0 ° C for 0.5 h. (Bromomethyl)benzene (78.92 g, 461.44 mmol, 1.20 eq.) was added at 0 ° C and the solution was stirred at room temperature overnight. The reaction was quenched with water. The solution was diluted with EtOAc (EtOAc (EtOAc)EtOAc. The crude product was purified by a silica gel column (with EA:PE (1:10)) to afford 266-2 (105 g, 78%).

266-2 (100 g, 285.38 mmol, 1.00 equiv), acetic acid (300 mL) and water (100 mL) were placed in a 1000 mL round bottom flask. The solution was stirred overnight at room temperature. The mixture was diluted with EtOAc (EtOAc EtOAc) The crude product 266-3 (64 g) was obtained as a pale yellow oil. ESI MS m/z: 333 [M+Na] ⁺ .

A solution of 266-3 (140 g, 451.11 mmol, 1.00 equiv) in MeOH (500 mL) was placed in a EtOAc EtOAc. A solution of sodium periodate (135.2 g, 632.10 mmol, 1.40 equiv) in water (1000 mL) was added. The solution was stirred at room temperature for 1 hr then diluted with EtOAc EtOAc. The solid was dried in an oven <RTI ID=0.0></RTI><RTI ID =0.0>

A solution of 266-4 (100 g, 359.32 mmol, 1.00 equiv) in tetrahydrofuran (500 mL) was placed in a 3000 mL round bottom flask at room temperature. Water (500 mL) was added. A NaOH solution (600 mL, 2N in water) was added to the mixture at 0 ° C, followed by aqueous formaldehyde (240 mL, 37%). The solution was stirred overnight at room temperature. The mixture was diluted with EtOAc (EtOAc EtOAc. The crude product was purified by EtOAc EtOAc ( EtOAc: EtOAc ) ESI MS m/z: 333 [M+Na] ⁺ .

A solution of 266-5 (76 g, 244.89 mmol, 1.00 equiv) in acetonitrile (1500 mL) was placed in a 3000 mL round bottom flask at room temperature. NaH (6.76 g, 281.67 mmol, 1.15 eq.) was added in several portions at 0 °C. The solution was stirred at 0 °C for 15 minutes, followed by the addition of (bromomethyl)benzene (48.2 g, 281.82 mmol, 1.15 eq.). The solution was stirred overnight at room temperature. The reaction was quenched with water, diluted with EA (3000mL), washed with aqueous ₄ Cl NH (3 × 500mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc ( EtOAc ( EtOAc ) ESI MS m/z: 423 [M+Na] ⁺ .

A solution of diethylaminosulfur trifluoride (6.6 mL, 2.00 equiv) in toluene (10 mL) was placed in a 250 mL round bottom flask at room temperature. Toluene (120 mL) containing 266-6 (10 g, 24.97 mmol, 1.00 eq.) was added at 0 °C. The solution was stirred at 60 ° C for 3 hours in an oil bath. The mixture was cooled to 0. EtOAc (EtOAc)EtOAc. The crude product was purified by EtOAc EtOAc ( EtOAc: EtOAc ( EtOAc ) ESI MS m/z: 425 [M+Na] ⁺ .

To a 250 mL 3-neck round bottom flask which was purified and maintained under N ₂ inert atmosphere was placed EtOAc EtOAc (EtOAc &lt;RTIgt; Acetic anhydride (6 mL) and sulfuric acid (0.05 mL) were added. The solution was stirred at room temperature for 2 hours. The mixture was then diluted with EtOAc EtOAc (EtOAc)EtOAc. The crude product was purified by EtOAc ( EtOAc: EtOAc ( EtOAc ) ESI MS m/z: 469[M+Na] ⁺ .

A solution of 266-8 (4 g, 8.96 mmol, 1.00 equiv), 10% Pd-C catalyst (4 g) in MeOH / DCM (25 mL / 25 mL) was placed in a purified 50 mL round bottom flask. About 3 atmospheres of H ₂ (gas) was introduced into the mixture. The solution was stirred at room temperature for 48 hours. The solid was collected by filtration <RTI ID=0.0>: < /RTI></RTI></RTI></RTI><RTIgt;

Pyridine (8 mL) containing 266-9 (2000 mg, 7.51 mmol , 1.00 equiv), Ac ₂ O (8 mL), 4-dimethylaminopyridine (183.2 mg, 0.20 equivalent) was placed in a 25 mL round bottom flask. The solution was stirred at room temperature for 3 hours. The reaction was a saturated solution of sodium bicarbonate. The solution was diluted with EtOAc (EtOAc)EtOAc. The crude product was purified by EtOAc EtOAc ( EtOAc ( EtOAc ) ESI MS m/z: 373 [M+Na] ⁺ .

A solution of 266-10 (300 mg, 0.86 mmol, 1.00 equiv) in dichloromethane (3 mL) was placed in a 25 mL round bottom flask. Trimethyldecanecarbonitrile (169 mg, 1.70 mmol, 2.00 equiv) was added at room temperature, followed by the addition of tetrachlorostannane (223 mg, 0.86 mmol, 1.00 equiv) at 0 °C. The solution was stirred at 0 ° C for 3 hours. The reaction was quenched with a saturated solution of sodium bicarbonate. The solution was diluted with EtOAc (EtOAc)EtOAc. The crude product was purified by EtOAc ( EtOAc: EtOAc ( EtOAc ) ¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm 5.67 to 5.75 (m, 2H), 4.25 to 4.78 (m, 5H), 2.19 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3 HI)

To a 25 mL round bottom flask was placed 266-11 (200 mg, 0.63 mmol, 1.00 eq.), NBS (223 mg, 1.25 mmol, 2.00 eq.). The solution was heated under reflux with a 250 W tungsten lamp for 3 hours and then cooled to room temperature. The reaction was quenched with a saturated solution of sodium bicarbonate. The solution was taken up in EtOAc (EtOAc)EtOAc. The crude product was purified by EtOAc ( EtOAc: EtOAc ( EtOAc ) ^{1 H-NMR (400MHz, CDCl} 3): δ ppm 6.03 (d, J = 4.8Hz, 1H), 5.90 (d, J = 4.8Hz, 1H), 4.29-4.30 (m, 4H), 2.25 (s, 3H), 2.15 (s, 3H), 2.25 (s, 3H).

N-(2-Phenoxy-1,2-dihydropyrimidin-4-yl)benzamide (54.3 mg, 2.00 eq.) was placed in a 25 mL round bottom flask which was purified and maintained in an argon atmosphere. And a solution of (NH ₄ ) ₂ SO ₄ (5 mg) in HMDS (3 mL). The solution was stirred overnight at 120 ° C in an oil bath. The solution was concentrated in vacuo and the residue was taken in EtOAc EtOAc. A solution of 266-12 (50 mg, 0.13 mmol, 1.00 eq.) in MeCN (1 mL) and EtOAc (32.5 mg, 1.00 eq. The solution was stirred at 80 ° C for 3 hours in a 10 mL sealed tube. After cooling to room temperature, the solution was diluted w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The crude product was purified by EtOAc EtOAc EtOAc ( EtOAc ) ESI MS m/z: 428[M+H] ⁺ .

A solution of 266-13 (100 mg, 0.23 mmol, 1.00 eq.) in ACN (3 mL) was placed in a 25 mL round bottom flask. 4-Dimethylaminopyridine (28.5 mg, 0.23 mmol, 1.00 eq.) and TEA (71 mg, 0.70 mmol, 3.00 eq.) were added followed by TPSCl (212.8 mg, 0.70 mmol, 3.00 eq.). The solution was stirred at room temperature for 3 hours and then concentrated in vacuo. The crude product 266-14 (200 mg) was obtained as a yellow oil.

A solution of 266-14 (140 mg, 0.10 mmol, 1.00 equiv) in ACN (3 mL) and EtOAc (3 mL) was placed in a 25 mL round bottom flask. The solution was stirred at 35 ° C for 4 hours in an oil bath. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (preparative HPLC-020): column, XBridge Prep C18 OBD column, 19×150 mm 5 μm 13 nm; mobile phase, water with 0.05% TFA and ACN (35.0% in 8 minutes up to 48.0% ACN); detector, mp, 266 (21.3 mg, 25%) as white solid. ESI MS m/z: 301.1 [M+1] ⁺ .

Placed 266-13 (50mg, 0.12mmol, 1.00 equiv) was added to 25mL round bottom flask, a saturated NH ₄ OH (2mL) and 1,4-dioxane (2mL) of a solution. The solution was stirred at room temperature for 2 hours. After concentration under reduced pressure, by preparative HPLC [(Prep-HPLC-020): column, XBridge Prep C18 OBD column, 19 × 150 mm 5 um 13 nm; mobile phase, water with 0.05% TFA and ACN (within 8 minutes) 35.0% up to 48.0% ACN); detector, nm] purification of the crude product obtained as a white solid of 265 (13.6mg, 39%). ESI MS m / z: 299.9 [ M-1] -.

Example 151

Nucleoside 267-1 (100 mg, 0.26 mmol) was dissolved in n-butylamine (2 mL) and kept at room temperature for 2 h. The solvent was evaporated and the residue was purified by RP HPLC on EtOAc EtOAc EtOAc. A linear gradient of 10 to 60% MeOH in 50 mM triethylammonium acetate buffer (pH 7.5) was used to dissolve. The corresponding fractions were combined, concentrated and lyophilized (3×) to remove excess buffer and 267 (20 mg, 25%). MS: m/z 308 [M-1].

Example 152

Compound 268-3 was prepared according to the procedure provided above. Compound 268 can be obtained using methods known to those skilled in the art, including those described in U.S. Publication No. 2012/0071434, filed on Sep. 19, 2011.

Example 153

2-(3) was added dropwise to a stirred solution of 269-1 (43.6% in dichloromethane, 345.87 g, 1.16 mol) in anhydrous DCM (1.0 L) over a period of 30 min. Phenylphosphine)ethyl propionate (400 g, 1.100 mol). The mixture was warmed to 25 ° C and stirred for 12 hours. The mixture was concentrated under reduced pressure. The residue was suspended in TMBE (2.0 L). The solids were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified on a EtOAc EtOAc (EtOAc: EtOAc) ¹ H-NMR (400 Hz, CDCl ₃ ), δ = 6.66 (dd, J = 6.8, 8.0 Hz, 1H), 4.81-4.86 (m, 1H), 4.11-4.21 (m, 3H), 3.60 (t, J = 8.4 Hz, 1H), 1.87 (d, J = 1.2 Hz, 3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H).

KMnO ₄ (90 g, 0.57 mol) was added to a stirred solution of 269-2 (100 g, 0.47 mol ) in acetone (2.0 L) at 0-5 °C. The mixture was stirred at 0-5 ° C for 2 hours. The reaction was quenched with a saturated solution of sodium sulfite (600 mL). After 2 hours, a colorless suspension formed. The solids were removed by filtration. The filter cake was washed with EA (300 mL). The filtrate was extracted with EA (3×300 mL). ₂ SO ₄ dried over anhydrous organic phase was dried Na. The organic phase was concentrated to dryness crystals crystals crystals crystals

To a stirred solution of 269-3 (50.0 g, 0.20 mol) and triethylamine (64.0 g, 0.63 mol) in anhydrous DCM (1.0 L) was added sulphur dichloride (36.0 g, 0.31 mol). After 30 minutes, the mixture was diluted with dichloromethane (500 mL) and washed with cold water ₂ SO ₄ dried over anhydrous organic phase was dried Na. The organic phase was concentrated under reduced pressure to give crude crystals. At 0 ℃, the catalyst was added TEMPO (500mg) and NaHCO ₃ (33.87g, 0.40mol) in dry acetonitrile containing the crude product of the. Sodium hypochlorite solution (10-13%, 500 mL) was added dropwise at 0 °C for 20 minutes. The solution was stirred at 25 ° C for 1 hour. The organic phase was concentrated and the aqueous extracted with dichloromethane (3×). ₂ SO ₄ dried over anhydrous organic phase was dried Na. The solvent was removed under reduced pressure to give 269-4 (5.

TBACl (155.4 g, 0.50 mol) was added to a stirred solution of 269-4 (62.0 g, 0.20 mol) in anhydrous dioxane (1.5 L) at 25 °C. The solution was stirred at 100 ° C for 10 hours. The mixture was cooled to 25 &lt;0&gt;C and treated sequentially with 2,2-dimethoxypropane (700 mL) and concentrated HCl (12N, 42mL). The mixture was stirred at 25 deg.] C for 3 hours and then concentrated under reduced pressure to obtain 269-5 (45.5g, crude) as a brown oil of the crude product, which was used without further purification in the next step.

The crude product 269-5 (45.5 g, 171 mmol) was dissolved in EtOAc (EtOAc) The mixture was stirred at 25 ° C for 16 hours. The solvent was removed under reduced pressure. The residue obtained was co-evaporated with toluene (3 ×) as a brown oil of the crude product 269-6 (24.6g, crude), which is used in the next step.

To the stirred solution of the crude product 269-6 (24.6 g, crude product) and DMAP (4.8 g, 40.0 mmol) in anhydrous pyridine (800 mL) was added benzalkonium chloride at 0 ° C over a period of 40 min. 84.0 g, 0.60 mol). The mixture was stirred at 25 ° C for 12 hours and then concentrated under reduced pressure. The residue was dissolved in EA (1.5 L). The solution was washed with 1.0 M HCl solution (400 mL) and brine (800 mL). ₂ SO ₄ dried over anhydrous organic phase was dried Na. The solvent was removed under reduced pressure to give a brown solid. The solid was suspended in MeOH (600 mL). After filtration, the filter cake was washed with MeOH. The filter cake was dried under reduced pressure to give 269-7 (40.0 g, 75.0%) as a white solid.

At -78 ℃, under N _2, a period of 30 minutes to 269-7 (7.0g, 18.04mmol) in dry THF (70mL) in the stirred solution was added dropwise tributyltin hydride - tert-butoxy Aluminum solution (2.7 mL, 1.0 M, 27.06 mmol). The mixture was stirred at -20 ° C for 1 hour. With saturated aqueous NH ₄ Cl The reaction was quenched and diluted with EA. After filtration, the filtrate was extracted with EA. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc: EtOAc )

At -20 ℃, under N _2, the PPh ₃ (1.34g, 5.12mmol) in CH ₂ Cl ₂ (5mL) was added in the 269-8 (1.0g, 2.56mmol) at room temperature. After stirring the mixture for 15 minutes, CBr ₄ (1.96 g, 5.89 mmol) was added portionwise while maintaining the reaction temperature at -25 to -20 ° C under N ₂ flow. After the addition was completed, the mixture was stirred at -17 ° C for 20 minutes. The reaction was treated with silicone. After filtration, the silicone pad was washed with CH ₂ Cl ₂ . The combined filtrate was purified by EtOAc ( EtOAc EtOAc ( EtOAc: EtOAc )

To a 0.25 L three-necked round bottom flask was charged 6-chloro-9H-indol-2-amine (5.5 g, 34.75 mmol) and anhydrous t-BuOH (45 mL). At room temperature under a stream of N _2, was added potassium tert-butoxide (3.89g, 32.58mmol) in portions to the solution. After 30 minutes, a solution of 269-9 (4.92 g, 10.86 mmol) in anhydrous acetonitrile (30 mL) was added over a period of 5 min. The mixture was slowly heated to 50 ° C and stirred for 12 hours. NH ₄ Cl and water mixture with a solid, then filtered through a short pad of diatomaceous earth. The pad was washed with EA and the filtrate was neutralized with 1.0 M aqueous HCl. The combined organic layers were dried over anhydrous Na ₂ SO _4. The organic phase was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc: EtOAc ) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ= 8.37 (s, 1H), 8.07-8.01 (m, 2H), 7.93-7.87 (m, 2H), 7.75-7.69 (m, 1H), 7.65- 7.53 (m, 3H), 7.41 (t, J = 7.8 Hz, 2H), 7.13 (s, 2H), 6.37 (d, J = 19.3 Hz, 1H), 6.26-6.13 (m, 1H), 4.86-4.77 (m, 1H), 4.76-4.68 (m, 2H), 1.3 (d, J = 20 Hz, 3H).

Compound 269-10 (700 mg, 1.29 mmol) was dissolved in MeOH (25 mL) EtOAc . The mixture was stirred at 50 ° C for 12 hours. The solvent was removed under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj

At 25 deg.] C containing the MeOH 7.0M NH ₃ (25mL) treating compound 269-11 (250mg, 0.477mmol) and stirred for 18 hours. Remove solvent at low pressure. By prep HPLC (NH ₄ HCO ₃ system) to give a white solid was obtained of 269 (85mg, 56.4%). MS: m/z 315.7 [M+H] ⁺ , 630.5 [2M+H] ⁺ .

Example 154

To 269 (50mg, 0.16mmol) and N- methylimidazole (50μL, 0.64mmol) in acetonitrile (1.5mL) was added in the ice-270-1 (0.1g, 0.28mmol) in of acetonitrile (0.15 mL) Solution. The mixture was stirred at 5 ° C for 1 hour. The reaction was quenched with EtOH and the mixture was concentrated. The evaporated residue was partitioned between EtOAc and EtOAc (EtOAc). The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried then dried over Na ₂ SO _4. Purification by RP-HPLC (A: water, B:MeCN) afforded 270 (30 mg, 30%) as white powder. MS: m/z 625 [M + 1].

Example 155

At 0 deg.] C (ice / water bath) to 271-1 (180mg, 0.16mmol) in dry CH added N- methylimidazole (53.4μL, 0.65mmol) in the ₃ CN (2.0mL) stirred solution. Addition of (cyclohexyloxy-L-alanine) chlorophosphonate (101 mg, 0.29 mmol) prepared according to the general procedure (McGuigan et al., J. Med . Chem. 2008 , 51 , 5807) in CH ₃ CN Solution in (0.5 mL). The solution was stirred at 0 to 5 ° C for 3 hours. N-methylimidazole (50 μL) and (cyclohexyloxy-L-alanine) chlorophosphonate (52 mg, dissolved in 0.5 mL of CH ₃ CN) at 0 ° C (ice/water bath) were sequentially added. The mixture was stirred at room temperature for 16 hours. The mixture was cooled to 0 to 5 ° C and diluted with EA. Water (5 mL) was added. Solution, NaHCO ₃ and washed with 1.0M aqueous citric acid and saturated brine, and dried over MgSO _4. The residue was purified on EtOAc (EtOAc: EtOAc (EtOAc)

Compound 271-2 (95mg, 0.11mmol) was dissolved in anhydrous CH ₃ CN (0.5mL), and was added in dioxane (77μL, 0.3mmol) 4N HCl at 0 to the 5 ℃. The mixture was stirred at room temperature for 30 minutes, and anhydrous EtOH (100 μL) was added. The solvent was evaporated at room temperature and co-evaporated with toluene (3×). In RP-HPLC (having a _{H 2 O / CH 3 CN (} 50-100% gradient)) and the residue was purified lyophilized to obtain a white foam of 271 (37.7mg, 52.5%). ESI-LCMS: m/z = 653.2 [M+H] ⁺ , 1305.4 [2M+H] ⁺ .

At -78 ℃, under N _2, to 271-A (56g, 0.144mol) in dry (600 mL) in of THF was added dropwise a solution of lithium hydride three - tert-butoxy aluminum solution (216mL, 1M, 0.216 mol) lasted for 30 minutes. The solution was stirred at -78 ° C to 0 ° C for 1 hour. The reaction was quenched with saturated NH ₄ Cl solution and extracted with EA (3 × 200mL). The combined organic layers were dried over anhydrous Na ₂ SO _4, filtered, and concentrated to obtain a colorless oil of 271-B (52g, 92% ).

At -20 ℃, under N _2, was added 271-B (34g, 0.087mol) with stirring to PPh ₃ (45.7g, 0.174mol) in CH ₂ Cl ₂ (200mL) was in the solution. The mixture was stirred for 15 minutes. CBr ₄ (58 g, 0.174 mol) was added dropwise while maintaining the temperature at -25 ° C to -20 ° C under a stream of N ₂ . The mixture was then stirred at -17 ° C for 20 minutes. The mixture was treated with silicone. The solution was filtered through a cold crucible column and washed with a cold dissolving agent (PE: EA = 50:1 to 4:1). The combined filtrate was concentrated under reduced pressure at room temperature to afford crude oil. By silica gel column (PE: EA = 50: 1 to 4: 1) to afford a colorless oil was obtained of 271-C (α- isomer, 24g, 61%). ¹ H-NMR (CDCl ₃ , 400 MHz), δ = 8.16 (d, J = 6.8 Hz, 2H), 8.1 (d, J = 7.6 Hz, 2H), 7.42 - 7.62 (m, 6H), 6.43 (s, 1H), 5.37 (d, J = 4.4 Hz, 1H), 4.68-4.86 (m, 3H), 1.88 (s, 3H).

A mixture of 6-Cl-guanosine (80.8 g, 0.478 mol) and t- BuOK (57 g, 0.509 mol) in t-BuOH (1 L) was stirred at 30-35 °C for 30 min. 271-C (72 g, 0.159 mol, 500 mL in MeCN) was added at room temperature and the mixture was heated to 70 ° C and stirred for 3 hours. The reaction was quenched with saturated NH ₄ Cl solution, and extracted with EA (3 × 300mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporation under low pressure. The residue was purified by a silica gel column (PE: EA = 4:1 to 2:1) to afford 271-D (14 g, 16%). ¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.93-8.04 (m, 4H), 7.90 (s, 1H), 7.30-7.50 (m, 6H), 6.53 (d, J = 8.8 Hz, 1H), 6.36 ( s, 1H), 5.35 (s, 2H), 5.06-5.10 (m, 1H), 4.81-4.83 (m, 1H), 4.60-4.64 (m, 1H), 1.48 (s, 3H).

To 271-D (14g, 25.9mmol) was added in DCM (15mL) in a solution of AgNO ₃ (8.8g, 51.8mmol) and collidine (6.3g, 51.8mmol) and MMTrCl (12.1g, 38.9mmol) . The mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (5 mL). After filtration, the filter was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by a silica gel column (PE: EA = 10:1 to 3:1) to afford 271-E (16 g, 80%). ¹ H-NMR (CDCl ₃ , 400 MHz) δ = 8.05-8.07 (m, 4H), 7.93 (s, 1H), 7.18-7.57 (m, 18H), 6.77 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 5.86 (s, 1H), 5.6 (s, 1H), 4.77 (d, J = 10.0 Hz, 1H), 4.67-4.76 (m, 1H), 4.55-4.59 (m, 1H), 3.75 (s, 1H), 1.06 (s, 3H).

Sodium (170 mg, 7.38 mmol) was dissolved in anhydrous EtOH (5 mL) at 70 °C and the solution was cooled to 0 °C. 271-E (1 g, 1.23 mmol) was added portionwise at 0 °C. The mixture was stirred at room temperature for 8 hours. CO ₂ for mixture was neutralized to pH 7.0, and the low-pressure concentrated. By prep _{HPLC (10% CH 3 CN /} H 2 O) was obtained residue was purified as a yellow solid of 271-1 (0.4g, 53%). ESI-MS: m/z 616 [M+H] ⁺ .

Example 156

Compound 272

Diisopropylethylamine was added to an ice-cold solution of bis(POM)triethylammonium phosphate (7 mmol, prepared from 2.3 g of bis(POM) phosphate and 1 mL of Et ₃ N) and 272-1 (1.36 g; 4.2 mmol) (3.6 mL; 21 mmol), BOP-Cl (2.68 g; 10.5 mmol) and 3-nitro-1,2,4-triazole (1.20 g; 10.5 mmol). The mixture was stirred at 0 ° C for 2 hours. The mixture was then diluted with EtOAc, washed with 1M citric acid, washed with saturated aqueous NaHCO ₃ and brine and dried over Na ₂ SO _4. In the silica gel column (with i-PrOH / CH ₂ Cl ₂ solvent system (gradient 2-12%)) was purified by the evaporated residue obtained was 272-2 (2.13g, 80%).

A solution of 272-2 (2.13 g) in 80% aqueous HCOOH (10 mL) was stirred at 45 ° C for 8 hr. The mixture was cooled and concentrated to give a residue. The residue with toluene and a few drops of Et ₃ N coevaporated MeOH. In the silica gel column (with MeOH: CH ₂ Cl ₂ (3-10% gradient)) purified the residue obtained by evaporation of a white foam of 272 (1.1g, 56%). MS: m/z = 565 [M-1].

Example 157

40-1 (1.78 g, 5 mmol) and Compound A (3.22 g, 5.5 mmol; prepared according to the procedure provided in WO 2008/82601 A2) were co-evaporated with pyridine and then dissolved in pyridine (70 mL). Pentylene chloride (1.22 mL; 10 mmol) was added dropwise at -15 ° C, and the mixture was stirred at -15 ° C for 2 hr. The mixture was diluted with CH _{2 2} Cl, washed with 0.5M NH ₄ Cl solution and brine, and dried over Na ₂ SO _4. The Silica column (with _{CH 2 Cl 2: i-PrOH} (4-10% B gradient)) purified the residue obtained by evaporation of 280-2 (2.1g, 50%).

Benzylamine (0.34 mL, 3.1 mmol) was added dropwise to a solution of 280-2 (0.51 g, 0.62 mmol) in CCl ₄ (6 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with 0.5M aqueous citric acid, washed with saturated aqueous NaHCO ₃ and brine and dried over Na ₂ SO _4. The Silica column (with _{CH 2 Cl 2: i-PrOH} (4-10% B gradient)) Purification of the residue obtained by evaporation of the 280-3 (0.46g, 80%).

A mixture of 280-3 (130 mg, 0.14 mmol) and 80% aqueous TFA (1.5 mL) was stirred at room temperature for 2 hr. The mixture was evaporated and co-evaporated with toluene. The Silica column (with _{CH 2 Cl 2: MeOH (4-12} % B gradient)) obtained residue was purified by 280 (32mg, 37%) a. MS: m/z = 620 [M + 1] ⁺ .

Example 158

A solution of Z-Ala-OH (111.6 mg, 0.5 mmol) in dry THF (2 mL) The mixture was stirred at 40 ° C for 1 hour under an Ar atmosphere. This solution was added to 44 (200mg, 0.33mmol), Et 3 N (72μL, 0.5mmol) and DMAP (4mg) in DMF (2mL) in the solution. The mixture was stirred at room temperature for 2.5 hours. The reaction was quenched by the addition of 1M EtOAc (2 mL) EtOAc. The organic layer was separated, washed with sodium bicarbonate and brine, dried over MgSO _4, filtered and concentrated. The residue was purified by column chromatography eluting elut elut elut elut elut elut

10% Pd/C (5 mg) was added to a solution of 281-1 (50 mg, 0.062 mmol) in anhydrous EtOH (2 mL), followed by 4N HCl (31 μL, 0.124 mmol), and the mixture was stirred under H ₂ atmosphere. hour. After the reaction was completed, the mixture was filtered through celite. The catalyst cake was washed with anhydrous EtOH. The washings and the filtrate were combined, and the solvent was evaporated in vacuo to afford 281 (33.3mg, 79. MS: m/z = 674.1 [M + H] ⁺ , 1347.2 [2M+H] ⁺ .

Example 159

A solution of Z-Gly-OH (105 mg, 0.5 mmol) in dry THF (2 mL) The mixture was stirred at 40 ° C for 2 hours, followed by stirring at 80 ° C for 30 minutes under an Ar atmosphere. This solution was added to 44 (200mg, 0.33mmol), Et 3 N (72μL, 0.5mmol) and DMAP (4mg) in DMF (2mL) in the solution. The mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of 1M EtOAc (2 mL) EtOAc. The organic layer was separated, washed with sodium bicarbonate and brine, dried over MgSO _4, filtered and concentrated. The residue was purified by column chromatography eluting eluting elut elut eluting

To a solution of 282-1 (75 mg, 0.094 mmol) in dry EtOAc (3 mL) EtOAc (EtOAc) The mixture was stirred under a H ₂ atmosphere for 3 hours. After the reaction was completed, the mixture was filtered through celite. The catalyst cake was washed with anhydrous EtOH. The washings and the filtrate were combined, and the solvent was evaporated in vacuo to afford 282 (44.3mg, 71. MS: m / z = 658.05 [ M + H] +, 1317.05 [M + H] +.

Example 160

Add L- alanine isopropyl ester hydrochloride (135mg, 0.8mmol) in the solution of 280-2 (223mg, 0.27mmol) in CCl ₄ (3mL) and added dropwise in Et ₃ N (0.22mL, 1.6mmol ). The mixture was stirred at room temperature for 1 hour. Followed by the mixture was diluted with CH ₂ Cl _2, washed with saturated aqueous NaHCO ₃ and brine and dried over Na ₂ SO _4. Silicon dioxide in the column (with _{CH 2 Cl 2: i-PrOH} (3-10% B gradient)) purified the residue obtained by evaporation of 283-1 (0.16g, 62%).

A mixture of 283-1 (100 mg, 0.11 mmol) and 80% aqueous TFA (3 mL) was stirred at room temperature for 2 hr. The mixture was then evaporated and co-evaporated with toluene. The Silica column (with _{CH 2 Cl 2: MeOH (4-10} % B gradient)) obtained residue was purified on 283 (31mg, 46%). MS: m/z = 644 [M + 1] ⁺ .

Example 161

Compounds 284 and 306

To (1.08g, 3.0mmol) in N, N 40-1 - was added CsCO dimethylacetamide (15mL) in a solution of ₃ (1.22g, 3.7mmol), the mixture was stirred for 15 min and at room temperature. Dichloromethyl chloromethyl phosphate (1 g, 3.0 mmol) was added, and the mixture was stirred at 40 ° C overnight. After cooling, the mixture was diluted with methyl t-butyl ether and washed with water (3×) and brine and dried over Na ₂ SO ₄ . Silicon dioxide in the column (with _{CH 2 Cl 2: i-PrOH} (3-10% B gradient)) purified the residue was evaporated to obtain crude 284-1 (580mg, 30%).

To a solution of bis(isopropoxycarbonyloxymethyl)phosphoric acid triethylammonium (1.8 mmol, prepared from 0.60 g of bis(isopropoxycarbonyloxymethyl)phosphate and Et ₃ N) in THF Add 284-1 (0.58 g, 0.9 mmol). The mixture was evaporated and made anhydrous by co-evaporation with pyridine and toluene. The evaporated residue was dissolved in dry THF (9 mL) and evaporated. Diisopropylethylamine (0.94 mL, 5.4 mmol) was added followed by BOP-Cl (0.69 g, 2.7 mmol) and 3-nitro-1,2,4-triazole (0.31 g, 2.7 mmol). The mixture was stirred at 0-5 deg.] C for 2 hours and was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ and brine, and dried over Na ₂ SO _4. Silicon dioxide in the column (with _{CH 2 Cl 2: i-PrOH} (3-10% B gradient)) purified the residue obtained by evaporation of 284-2 (0.77g, 89%).

To a solution of 284-2 (50 mg; 0.05 mmol) in EtOH (2.5 mL) was added 10% Pd / C (8 mg), and the mixture was stirred for 1 hour under H ₂ (at atmospheric pressure). The mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was treated three hours with 80% HCOOH aqueous solution (2.5mL), followed by evaporation and by RP-HPLC (A: 50mM TEAA aqueous solution, B: 50mM TEAA containing the MeCN) to afford a white solid of 284 (22mg, 44 %). MS: m/z = 713 [M + 1] ⁺ .

To a solution of 284 (14 mg, 0.02 mmol) in EtOH (0.3 mL), EtOAc (EtOAc) The mixture was allowed to warm to room temperature and the resulting white solid was centrifuged. Discard the supernatant layer. Solid was washed with EtOH (0.3mL) and the centrifugation process 306 (8mg). MS: m/z = 713 [M + 1] ⁺ .

Example 162

Concentrated H ₂ SO ₄ (56 mL) was added dropwise to a stirred suspension of 285-1 (300 g, 1.86 mol) in acetone (4L). The mixture was stirred at room temperature for 3 hours. NaHCO ₃ and the mixture was filtered and the solids. The filtrate was evaporated under reduced pressure to obtain a colorless oil of 285-2 (381g, crude), which was used without further purification in the next step.

Imidazole (191 g, 2.82 mol) and TBSCl (564 g, 3.76 mol) were added to a stirred solution of 285-2 (380 g, crude product, 1.88 mol) in anhydrous DCM (2L). The mixture was stirred at room temperature for 12 hours and then filtered. The filtrate was concentrated to dryness and purified EtOAc EtOAcjjjjjjjj

DIBAL-H (710 mL, 0.71 mol, 1.0 M in toluene) was added to a solution of 285-3 (150 g, 0.47 mol ) in anhydrous THF (2 L). With saturated aqueous NH ₄ Cl The reaction was quenched, followed by filtration. The filtrate was extracted with EA and washed with brine. The organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by EtOAc EtOAc ( EtOAc )

Isopropyltriphenylphosphonium iodide (422.8 g, 0.98 mol) was suspended in dry THF (1 L) and cooled to 0 °C. The BuLi solution (2.5 M in THF, 391 mL, 0.98 mol) was added dropwise over 0.5 hour. The dark red solution was kept at 0 °C for 0.5 hours and 285-4 (207.5 g, 0.65 mol) of THF (1 L) was slowly added over 2 hours. The mixture was warmed to ambient temperature and stirred for 12 hours. With saturated aqueous NaHCO ₃ The reaction was quenched. The precipitated solid was removed by filtration. The filtrate was diluted with EA and washed with brine. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The filtrate was concentrated under reduced pressure, and the residue was purified eluted eluted elut elut elut elut elut eluting

IBX (7.9 g, 28.4 mmol) was added to a stirred solution of 285-5 (4.9 g, 14.2 mmol). The mixture was refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography eluting with EtOAc ( EtOAc )

LiHMDS (THF) was added dropwise to a stirred solution of 285-6 (2.0 g, 5.8 mmol) and difluoromethylphenylhydrazine (2.24 g, 11.7 mmol) in anhydrous DMF (50 mL). Medium 1.0M, 11.7 mL). After stirring at -78 ℃ 2 hours, saturated aqueous NH ₄ Cl The reaction was quenched. The mixture was then stirred at 0 ° C for 30 minutes. The organic phase was separated and the aqueous phase was extracted with EA. , Washed with brine and dried the combined organic phases over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The residue was purified on EtOAc ( EtOAc EtOAc: EtOAc ) ¹ H-NMR (CDCl ₃ , 400 MHz) δ = 8.01 - 7.97 (m, 2H), 7.74 - 7.70 (m, 1H), 7.61 - 7.57 (m, 2H), 5.80 (d, J = 1.6 Hz, 1H) , 4.26 (d, J = 11.2 Hz, 1H), 4.08 (s, 1H), 4.03 (d, J = 11.2 Hz, 1H), 3.86 (s, 1H), 1.82 (s, 3H), 1.69 (s, 3H), 1.54 (s, 3H), 1.41 (d, J = 12.4 Hz, 6H), 0.89 (s, 9H), 0.09 (d, J = 9.6 Hz, 6H).

C was added Mg (3.6g, 149.8mmol) to 285-7 in the (4.0g, 7.5mmol) in DMF (80mL) and H ₂ O (16mL) was added, followed by HOAc (13.5g, 224.7mmol). The mixture was stirred at room temperature for 6 hours. The mixture was poured into ice water and filtered. The filtrate was extracted with EA. , Washed with brine and dried the combined organic phases over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness and EtOAc EtOAc m . ¹ H-NMR (CDCl ₃ , 400 MHz) δ=5.88-5.74 (m, 2H), 3.98-3.78 (m, 3H), 3.30 (s, 1H), 3.08 (s, 1H), 1.83 (s, 3H) , 1.70 (s, 3H), 1.41 (s, 3H), 1.35 (d, J = 23.2 Hz, 6H), 0.90 (d, J = 4.4 Hz, 9H), 0.08 (d, J = 7.6 Hz, 6H) .

A solution of TBAF in THF (6 mL, 1.0 M) was added to EtOAc EtOAc ( EtOAc, EtOAc . The mixture was concentrated to dryness and purified EtOAc EtOAc EtOAc EtOAc EtOAc

At 0 ℃, to 285-9 (415mg, 1.5mmol) in dry DCM (7.5mL) was added in the Et ₃ N (224mg, 2.2mmol) and BzCl (248mg, 1.7mmol). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, with saturated aqueous NaHCO ₃ The reaction was quenched and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was evaporated, and the residue was purified mjjjjjjjjjjj

Turned blue bubbled O ₃ until the solution stirred solution of 285-10 (440mg, 1.2mmol) in dry DCM (10mL) was at -78 ℃. O ₂ was then bubbled through the reaction until the solution became colorless. The organic layer was evaporated to give 285-11 (430mg, crude), which was used without further purification in the next step.

The 285-11 (441 mg, 1.2 mmol) of 90% TFA (6 mL) was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

At 0 ℃, the medium was added to 285-12 (404mg, 1.3mmol) in dry DCM (6mL) solution of _{Et 3 N (1.0g, 10.2mmol)} , DMAP (44mg, 0.4mmol) and BzCl (1.0g, 7.6 mmol). The mixture was stirred at room temperature for 4 hours. With saturated aqueous NaHCO ₃ The reaction was quenched and extracted with DCM. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The filtrate was evaporated, and the residue was purified mjjjjjjjjjjjjjjj

N,O-bis(trimethyldecyl)acetamide (680 mg, 3.3 mmol) was added to a stirred solution of uracil (190 mg, 1.7 mmol) in chlorobenzene (2.6 mL). The solution was stirred at 130 ° C for 30 minutes and then cooled to ambient temperature. SnCl ₄ (770 mg, 3.5 mmol) was slowly added dropwise to a solution of 285-13 (536 mg, 0.8 mmol) in chlorobenzene. The mixture was heated to reflux for 30 minutes. By saturated aqueous reaction was quenched with NaHCO _3, and extracted with EA. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The filtrate was evaporated, and EtOAc EtOAc m.

With 7.0M NH MeOH ₃ containing the processed 285-14 (80mg, 0.1mmol). The mixture was stirred at room temperature for 12 hours. Remove solvent at low pressure. By silica gel column chromatography (5% MeOH in the DCM) is obtained residue was purified as a white solid of 285 (36mg, 90.6%). ESI-LCMS: m / z 309.09 [M + H] +; 331.07 [M + Na] +.

Example 163

At 0 ℃, to 51 (240mg, 0.8mmol) in trimethyl phosphate (4mL) are added to a mixture of POCl ₃ (0.18mL, 1.6mmol), and the mixture was stirred at 0 ℃ 90 minutes. Add L- alanine isopropyl ester hydrochloride (0.24g, 1.4mmol) and _{Et 3 N (0.6mL, 4.3mmol)} . The mixture was allowed to warm to room temperature and stirring was continued for 1.5 hours. With 0.5M TEAA The reaction was quenched with aqueous, and by RP-HPLC (A: 50mM TEAA aqueous solution, B: 50mM TEAA containing the MeCN) obtained mixture was purified 286-1 (75mg).

Mixture of 286-1 (52 mg, 0.1 mmol), DIPEA (0.11 mL, 0.6 mmol) and isopropoxycarbonyloxymethyl iodide (77 mg, 0.3 mmol) in NMP (1.1 mL) hour. The mixture was diluted with tert-butyl methyl ether, washed with saturated aqueous NaHCO ₃ and brine and dried over Na ₂ SO _4. The Silica column (with _{CH 2 Cl 2: MeOH (4-10} % B gradient)) was evaporated and the residue was purified to obtain 286 (12mg, 20%) a. MS: m/z = 600 [M + 1] ⁺ .

Example 164

Add DMAP (4 mg, 0.033 mmol), N-Cbz-O-benzyl-L to a solution of 44 (200 mg, 0.33 mmol) in anhydrous DCM (6 mL). - Serine (164 mg, 0.5 mmol) and EDC (100 mg, 0.52 mmol). The mixture was stirred at room temperature for 40 hours. Using an ice / water bath cooled mixture was diluted with DCM (10mL), Cl and washed with saturated NH _4, dried over MgSO _4, filtered and concentrated. The residue was purified by column chromatography eluting elut elut elut elut elut elut elut

Add 10% Pd/C (11.4 mg) to a solution of 287-1 (68.7 mg, 0.075 mmol) in anhydrous EtOH (2.5 mL), followed by 4N HCl (38 μL, 0.15 mmol) and in H ₂ atmosphere The mixture was stirred for 3 hours. After the reaction was completed, the mixture was filtered through celite. The catalyst cake was washed with anhydrous EtOH. The washings and the filtrate were combined, and the solvent was evaporated in vacuo to afford 287 (40.1 mg, 77. MS: m/z = 690.1 [M+H] ⁺ .

Example 165

To a solution of Compound B (0.84 g, 2 mmol; according to Villard et al. Bioorg . Med . Chem . (2008) 16: 7231-7329) and Et ₃ N (0.61 mL, 4.4 mmol) in THF at -78 °C A solution of N,N -dichloroaminodiisopropyl phosphate (184 μL, 1 mmol) in THF (7 mL) was added dropwise. The mixture was warmed and stirred at room temperature for 2 hours. The solid was filtered off. The filtrate was concentrated and silica gel column (with hexanes _{+ 1% Et 3 N: EtOAc} (1-20% B gradient)) to afford compound C (0.38g) on.

Add 5-ethylthio-1H-tetrazole (0.25 M in MeCN; 1.2 mL, 0.3 mmol) to a mixture of 40-1 (53 mg, 0.15 mmol) and Compound C (0.17 g, 0.17 mmol) in MeCN (1 mL) ). The mixture was stirred at room temperature for 1 hour and then cooled to -40 °C. Was added MCPBA (77%; 42mg, 0.19mmol ) in the ₂ Cl ₂ (0.5mL) in a solution of CH. The mixture was allowed to warm and stirred at room temperature for 30 minutes. The reaction was treated with an aqueous solution containing 4% NaHCO _{3 (1mL) 4% Na 2 S} 2 O 3 aqueous solution and the quenched with _{diluted 2} Cl CH. The organic layer was washed with saturated aqueous NaHCO ₃ and with brine, and dried over Na ₂ SO _4. In the silica gel column (with hexanes: EtOAc (30-100% B gradient)) was evaporated and the residue was purified to obtain 288-1 (150mg, 81%) a.

A solution of 288-1 (120 mg, 0.1 mmol) in 80% aqueous TFA (5 mL) was kept at room temperature for 3 hr. The mixture was concentrated and the residue was co-evaporated with toluene. The Silica column (with _{CH 2 Cl 2: MeOH (4-10} % B gradient)) to obtain crude material was purified on 288 (25mg, 36%). MS: m/z = 691 [M + 1] ⁺ .

Example 166

DMAP (244 mg, 1.98 mmol) and Z-Val-OH (502 mg, 1.98 mmol) were added successively to a mixture of DCC (412 mg, 1.98 mmol) in DMF (1 mL), followed by 44 (200 mg, 0.183 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated using a rotary evaporator until the 1⁄2 initial volume was reached. Add EA, and the mixture was washed with water and brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated in vacuo to obtain a residue. The residue was purified by EtOAc (EtOAc:EtOAc)

To a solution of 289-1 (68 mg, 0.064 mmol) in EtOAc (EtOAc) The mixture was stirred under a H ₂ atmosphere for 1.5 hours. The mixture was filtered through celite and the catalyst cake was washed with anhydrous EtOH. The washing liquid and the filtrate were combined. The solvent was removed in vacuo to afford 289 (4. MS: m/z = 801.25 [M+H] ⁺ .

Example 167

DCC (65 mg, 0.32 mmol), isobutyric acid (28 μl, 0.32 mmol) and DMAP (18 mg, 0.144 mmol) were added to a solution of 290-1 (40 mg, 0.144 mmol) in DMF (2 mL). The mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate was concentrated to a 1⁄2 initial volume using a rotary evaporator. Followed by 25% DMF / H ₂ O mixture was diluted and purified using CH ₃ CN and water on a reverse phase HPLC (C18). It was lyophilized to give 290 (17.5 mg, 29%) as white powder. MS: m/z 416.1 [M + H] ⁺ .

Example 168

Compound 291

To a solution of 290-1 (50 mg, 0.18 mmol) in EtOAc (EtOAc m. The mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate was concentrated to a 1⁄2 initial volume using a rotary evaporator. Followed by 25% DMF / H ₂ O mixture was diluted and purified using CH ₃ CN and water on a reverse phase HPLC (C18). The 291 (30.2 mg, 43%) was obtained as a white powder. MS: m/z 390.1 [M + H] ⁺ , 388.05 [MH] ^- .

Example 169

To a solution of 75 (20 mg, 0.073 mmol) in EtOAc (EtOAc) The mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate was concentrated to a 1⁄2 initial volume using a rotary evaporator. Followed by 25% DMF / H ₂ O and the mixture was diluted using 25-95% CH ₃ CN in reverse phase HPLC (C18): water purification. It was lyophilized to obtain 292 (12.1 mg, 38.7%) as a white powder. MS: m/z 430.15 [M + H] ⁺ , 428.10 [MH] ^- .

Example 170

Compound 293

To a solution of 75 (20 mg, 0.073 mmol) in EtOAc (EtOAc) The mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate was concentrated to a 1⁄2 initial volume using a rotary evaporator. The mixture followed by 25% DMF / diluted with H ₂ O, and using 25-95% CH ₃ CN in reverse phase HPLC (C18): water purification. The 293 (14.1 mg, 48%) was obtained as a white powder. MS: m/z 402.1 [M + H] ⁺ .

Example 171

To a solution of compound D (0.9 g, 6.0 mmol; according to Qing et al. Org. Lett. (2008) 10: 545-548) and POCl ₃ (0.55 mL, 6.0 mmol) in diethyl ether (9 mL) at -78 °C Et ₃ N (0.84 mL, 6.0 mmol) was added to the mixture. The mixture was allowed to warm to room temperature for 2 hours. The mixture was then filtered and the solid was washed with Et ₂ O. The combined filtrate was evaporated and the crude compound E was used without purification.

Add Et ₃ N (1.67 mL, 1.2 mmol) to a solution of the crude compound E and L- propyl propylamine hydrochloride (1.0 g, 6.0 mmol) in CH ₂ Cl ₂ (15 mL) ). The mixture was warmed and stirred at room temperature for 2 hours. The mixture was diluted with hexane and filtered through a pad of silicon dioxide, silicon dioxide with CH ₂ Cl ₂ pad: 1 Chedi washed with: 1 hexanes. The combined filtrate was concentrated and purified on a silica column (hexane:EtOAc (5-50% B gradient)) to afford compound F (0.78 g, 2 step 38%).

To a solution of 40-1 (0.36 g, 1.0 mmol) in THF (EtOAc) (EtOAc) A solution of compound F (0.78 g, 2.2 mmol) in THF (2 mL) With saturated aqueous NH ₄ Cl The reaction was quenched then diluted with EtOAc. Separate the two layers. The organic layer was washed with water and brine, and dried over Na ₂ SO _4. In the silica gel column (with _{CH 2 Cl 2: i-PrOH} (3-10% B gradient)) purified the residue obtained by evaporation of 294-1 (0.50g, 74%).

A solution of 294-1 (0.28 g, 0.4 mmol) in 80 TFA aqueous (4 mL) was stirred at room temperature for 4 hr. The mixture was evaporated and co-evaporated with toluene. The Silica column (with _{CH 2 Cl 2: MeOH (4-10} % B gradient)) obtained residue was purified 294-2 (0.17g, 68%).

To a solution of 294-2 (85 mg, 0.14 mmol) in EtOAc (3 mL) EtOAc (EtOAc) The mixture was stirred under H ₂ (atmospheric pressure) for 105 minutes. The mixture was then filtered through a pad of diatomaceous earth. Treated with Et ₂ O evaporated and the residue was obtained as a white solid of 294 (55mg, 63%). MS: m/z = 589 [M + 1] ⁺ .

Example 172

Compound 295

295-1 (120g, 0.26mol) and IBX (109g, 0.39mol) in a mixture of CH ₃ CN (2.0L) was heated to reflux and stirred for 12 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated at low pressure and used directly in the next step.

295-2 (130 g, crude product, 0.26 mol) was co-evaporated with anhydrous toluene (3×) to remove H ₂ O. Vinyl magnesium bromide (700 mL, 0.78 mol, 1.0 N in THF) was added dropwise to a solution of 295-2 in THF (300 mL) over 30 min. The mixture was stirred at 25 ° C for about 1 hour and verified by LCMS trace. When the starting material was consumed, the mixture was poured into a saturated aqueous solution of NH ₄ Cl and extracted with EA (3×300 mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated to a low pressure to obtain a crude intermediate, without further purification.

To this crude intermediate product (170g, 0.346mol) was added in dry CH ₂ Cl ₂ in a solution of TEA (105g, 1.04mol) and DMAP (84g, 0.69mol), and the mixture was stirred at room temperature. Benzamidine chloride (146 g, 1.04 mol) was slowly added at room temperature. After stirring at room temperature for 12 hours, the mixture was diluted with CH ₂ Cl ₂ and then washed with NaHCO ₃ sat. The combined aqueous phases were extracted with DCM (100 mL). The combined The organic phase was dried over anhydrous Na ₂ SO _4, filtered and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = EtOAc = EtOAc )

The uracil (treated twice by toluene) mixture of ₃ CN (200mL) and NOBSA (81.4g, 0.4mol) in CH stirred to reflux for 1.5 hours. After the mixture was cooled to room temperature, containing 295-3 (59g, 0.1mol, by treatment toluene) of CH ₃ CN (100mL). The mixture was treated with TMSOTf (155 g, 0.7 mol) and then warmed to 60-70 °C for 12 hours. LCMS showed no starting material remaining. The mixture was poured into a NaHCO ₃ (saturated) solution. Precipitate the desired product. After filtration, pure 295-4 (40 g, 69%) was obtained as a white solid.

Add PMBCl (16 g, 0.1 mol) to a solution of 295-4 (50 g, 0.086 mol), K ₂ CO ₃ (17.8 g, 0.13 mol) in DMF (500 mL) at 0 ° C, and at 25 ° C The mixture was stirred for 12 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The crude product 295-5 (65 g) was obtained and used directly in the next step.

A mixture of 295-5 (65 g, 0.086 mol) and NaOMe (16.8 g, 0.3 mol) in MeOH: DCM (4:1, LCMS showed no starting material remaining. The reaction was quenched with dry ice. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc

NaH (10.5 g, 0.26 mol) was slowly added to a solution of 295-6 (25.5 g, 0.065 mol) in DMF under ice bath, and the mixture was stirred for 30 min. BnBr (36.3 g, 0.21 mol) was added, and the mixture was stirred at 25 ° C for 12 hours. TLC showed the disappearance of the starting material. The reaction was purified by NH ₄ Cl was quenched with saturated aqueous and extracted with EtOAc (3 × 100mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by column chromatography (PE: EA = 5:1 to 3:1 to 1:1) to afford 295-7 (20 g, 46%).

OsO ₄ (2.6 g, 0.01 mol) was added to a solution of 295-7 (20 g, 0.03 mol), NMMO (7 g, 0.06 mol) in THF:H ₂ O (5:1, 100 mL) at 25 ° C. The mixture was stirred at 25 ° C for 24 hours. The reaction was quenched with saturated ₂ S ₂ O ₃ Na solution and extracted with EtOAc (3 × 100mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The diol product residue was used directly in the next step.

_{H 2 O:: THF (:} 30mL: 170mL 50mL) was added in the NaIO ₄ (9.6g, 0.045mol), and stirred at 25 deg.] C solution of diol product mixture for 2 hours (0.03 mol) in MeOH. After filtering the white solid, the filtrate was used directly in the next step.

The solution was treated with NaBH ₄ (1.8 g, 0.048 mol) at 0 ° C and stirred at 25 ° C for 30 min. The reaction was quenched with HCl (1N) and pH was adjusted to 7-8. The solution was extracted with EtOAc (3×50 mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by column chromatography (PE: EA = 6:1 to 4:1) to afford 295-8 (12 g,

MsCl (3.1 g, 27 mmol) was added to a solution of 295-8 (14 g, <RTI ID=0.0></RTI></RTI><RTIgt; LCMS showed no starting material remaining. By the reaction was quenched with saturated aqueous NaHCO ₃ and extracted with DCM (3 × 100mL). Solution was washed with a solution of HCl (0.2N), dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by column chromatography (PE: EA = 10:1 to 5:1) to afford OMs-product (14 g, 90%).

The OMs-product (6.1 g, 8.21 mmol) was dissolved in TBAF (Alfa, 1N in THF, 120 mL) and the mixture was stirred at 70-80 ° C for 3 days. LCMS showed 50% of the starting material was converted to the desired product. Concentrate the mixture at low pressure. The residue was dissolved in EtOAc (100 mL). With the solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified by column chromatography (PE: EA = 10:1 to 5:1) to afford 295-9 (1.3 g, 24%).

Was added CAN (15.5g, 28.3mmol) in a solution of (1,52mL v:: v = 3 ), and the mixture was stirred overnight at rt: to 295-9 (6.3g, 9.45mmol) in CAN H ₂ O . The reaction was quenched with water and extracted with EtOAc EtOAc. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc .

TPSCl (627 mg, 2.07 mmol) was added to a solution of 295-10 (566 mg, 1.04 mmol), EtOAc (EtOAc, EtOAc, EtOAc) The mixture was stirred at room temperature for 2 hours. The mixture was treated with _{NH 3 ˙H 2 O (10mL)} , and stirred overnight at rt. TLC showed the reaction was complete. Low pressure concentrated solution. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc

At -70 ℃, to 295-11 (200mg, 0.37mmol) in anhydrous DCM (0.5mL) was added in the BCl ₃ (2.5mL, DCM in 1N), and stirred at -70 ℃ mixture for 2 hours. TLC showed no material remaining. The reaction was quenched with MeOH at -70 ° C and concentrated directly at 40 ° C. The residue was dissolved in H ₂ O, and washed 3 times with EtOAc. The lyophilized aqueous phase gave 295 (91 mg, 89%) as white solid. ESI-LCMS: m/z 276.1 [M+H] ⁺ .

Example 173

At 20 ℃, under N _2, to 296-1 (8.2g, 15.3mmol) in anhydrous CH added IBX (4.7g, 16.8mmol) in the ₃ CN (150mL) stirred solution. The suspension was heated to 90 ° C to 100 ° C and stirred at this temperature for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. Residue 296-2 (8.2 g, crude) was used in the next step without further purification.

To a solution of 296-2 (8.2 g, 15.4 mmol ) in 1,4-dioxane (150 mL) was added EtOAc (15.4 mL, 2M, 30.8 mmol). The mixture was stirred at this temperature for 10 hours. The solution was neutralized with AcOH to pH = 7, followed by addition of EtOH at 0 ℃ (50mL) and NaBH ₄ (5.8g, 154.3mmol). The mixture was stirred at this temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic phase was washed with brine the combined, dried over anhydrous MgSO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

296-3 (480 mg, 0.8 mmol) was co-evaporated with toluene (2×). The residue was dissolved in dry EtOAc (5 mL)EtOAc Tf ₂ O (481 mg, 187 mmol) was added dropwise at 0 ° C over 10 min. The mixture was stirred at this temperature for 40 minutes. The mixture was purified by column chromatography ( EtOAc EtOAc EtOAc )

At 0 deg.] C, under N ₂ atmosphere, to 296-4 (602.0mg, 0.72mmol) in dry was added NaH (34.8mg, 0.87mmol) (8mL ) in a solution of DMF. The reaction was stirred at 20 ℃ for 1 hour, then at 0 deg.] C, was added NaN ₃ (1.59g, 2.5mmol) under N ₂ atmosphere. The mixture was stirred at 20 ° C for 2 hours. The reaction was quenched with water EtOAc (EtOAc) The combined organic layers were washed with brine, dried over Na ₂ CH ₄ and filtered. The filtrate was concentrated under reduced pressure to dryness. Residue 296-5 (431 mg, crude) was used in the next step without further purification.

A solution of 296-5 (431 mg, crude) in 1,4-dioxane (14 mL). The mixture was stirred at the same temperature for 3 hours. The mixture was diluted with EA (20 mL). The organic layer was washed with brine, dried MgSO ₄ The residue was purified by EtOAc EtOAc (EtOAc:EtOAc)

At 30 ℃, under N ₂ atmosphere, was added to the TBSCl of 296-6 (406.0mg, 0.68mmol) in anhydrous DMF (8mL) solution (198.7mg, 1.3mmol) and imidazole (119.7mg, 1.8mmol) . The solution was stirred at this temperature for 3 hours. The solution was diluted with EA (20 mL) and washed with water and brine. The organic phase was dried over MgSO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

At 30 ℃, to 296-7 (405.0mg, 0.57mmol) in dry the CH ₃ CN (6mL) was added 2,4,6-triisopropylbenzenesulfonyl 1-sulfonic acyl chloride (343.3mg , 1.13 mmol), DMAP (138.5 mg, 1.1 mmol) and TEA (114.7 mg, 1.1 mmol). The mixture was stirred at this temperature for 9 hours. NH ₃ ̇H ₂ O (4 mL) was added, and the mixture was stirred for 3 hr. The mixture was diluted with EA (20 mL) and brine. The organic layer was dried over Na ₂ SO _4, and concentrated under low pressure. The residue was purified by EtOAc EtOAc (EtOAc)

296-8 (380.0 mg, 0.54 mmol) was dissolved in 80% HCOOH (25 mL), and the mixture was stirred at 30 ° C for 12 hr. The reaction was quenched with EtOAc andEtOAc By silica gel chromatography (10% MeOH in the DCM) is obtained residue was purified white foam of 296 (144.0mg, 83.93%). ESI-MS: m / z 319.1 [M + H] +; 637.2 [2M + H] +.

Example 174

Compound 297

TsOH ̇H ₂ O was added in one portion to a solution of 297-1 (30 g, 122.85 mmol) and 1,1-dimethoxycyclopentane (86 g, 660.93 mmol) in DCE (200 mL) at room temperature. (2.34 g, 12.29 mmol). The mixture was heated to 70 ° C and stirred for 14 hours. TLC showed the reaction was complete. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc :

At room temperature to 297-2 (20g, 64.45mmol) in dry CH of the ₃ CN (200mL) was added IBX (19.85g, 70.9mmol). The mixture was refluxed for 18 hours and then cooled to 0 °C. The precipitate was filtered off, and the filtrate was concentrated to obtain a yellow solid of the crude product 297-3 (20g, 100%).

To a solution of 297-3 (20 g, 64.87 mmol) in 1,4-dioxane (200 mL), EtOAc (EtOAc) The mixture was stirred at room temperature overnight, then neutralized with AcOH to pH = 7. At 20 ℃ solution was treated with NaBH ₄ (4.91g, 129.74mmol). The mixture was stirred for 1.0 hour at room temperature with saturated aqueous NH ₄ Cl The reaction was quenched. The mixture was extracted with EA (3 s 200 mL). Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

Pyridine (10.46 g, 132.20 mmol) and Tf ₂ O (8.21 g, 29.08 mmol) were added dropwise to 297-4 (4.5 g, 13.22 mmol) EtOAc. . The mixture was stirred at the same temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified on a silica gel column ( EtOAc: EtOAc = EtOAc )

At 0 ℃, under N _2, to 297-5 (5g, 8.27mmol) in dry was added NaH (396.96mg, 9.92mmol) DMF ( 25mL) in the stirred solution. The solution was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The solution of 297-6 was used in the next step without any further treatment.

At 0 deg.] C, under N ₂ atmosphere, the solution was stirred solution of 297-6 (3.75g, 8.25mmol) was added _{NaN 3 (1.5g, 2.50g, 38.46mmol} ). The solution was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. Residue 297-7 was used in the next step without further purification.

NaOH (8.25 mL, 16.50 mmol, 2.0 M in water) was added to a solution of 297-7 (2.87 g, 8.25 mmol) in anhydrous 1,4-dioxane (30 mL). The mixture was stirred at room temperature for 3 hours. TLC showed the reaction was complete. The mixture was diluted with EA. The solution was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. The residue was purified on a silica gel column (PE: EA = 10:1 to 2:1) to afford 297-8 (2 g, 66.4%) as a white foam. ¹ H-NMR (DMSO, 400 MHz), δ = 9.02 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 5.75 - 5.77 (m, 1H), 5.57 (d, J = 3.6 Hz, 1H) ), 5.13-5.16 (m, 1H), 4.90 (d, J = 6.4 Hz, 1H), 3.79-3.85 (m, 2H), 5.51-5.56 (m, 2H), 3.06-3.09 (m, 1H), 2.05-2.09 (m, 2H), 1.65-1.75 (m, 6H).

297-8 (2 g, 5.47 mmol ) was dissolved in 80% aqueous HCOOH (20 mL) and mixture was warmed to 60 &lt;0&gt;C for 2 h. Evaporate the mixture at low pressure. The residue was dissolved in MeOH and the pH was adjusted to 7 to 8 using NH ₃ ̇H ₂ O. The mixture was stirred for 10 minutes and then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

Diphenyl carbonate (157.49 mg, 735.20 μmol) and NaHCO ₃ (28.06 mg, 0.334 mmol) were added to a solution of 297-9 (1.00 g, 3.34 mmol) in DMF (5 mL). The mixture was stirred for 16 hours. TLC showed the reaction was complete. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc : ¹ H-NMR (DMSO, 400 MHz), δ = 8.49 (s, 1H), 7.83 (d, J = 7.2 Hz, 4H), 6.46 (s, 1H), 6.31 (d, J = 4.8 Hz, 1H), 5.84 (d, J = 6.8 Hz, 1H), 5.27 (d, J = 5.6 Hz, 2H), 4.43 (s, 1H), 3.53 (d, J = 12.8 Hz, 1H), 3.43 (d, J = 13.2) Hz, 1H), 3.12 (d, J = 11.2 Hz, 1H).

At room temperature to 297-10 (2g, 7.11mmol) and AgNO ₃ (1.81g, 10.67mmol) in Py (20mL) was added in one portion in the DMTrCl (3.61g, 10.67mmol). The mixture was stirred at room temperature for 12 hours. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure and EtOAc EtOAc ( EtOAc:EtOAc :

NaOH (5 mL, 2.0 N) was added in one portion to a solution of 297-11 (1.5 g, 2.57 mmol) in EtOH (5 mL). The mixture was stirred at room temperature for 0.5 hours. TLC showed the reaction was complete. The aqueous phase was extracted with EA (3 x 60 mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo was obtained 297-12 (1.50g, 97%) of a yellow solid.

At room temperature, to AC (6mL) in a solution of 297-12 (1.50g, 2.49mmol) in one portion Py ₂ O (3mL). The mixture was stirred at room temperature for 12 hours. TLC showed the reaction was complete. The mixture was concentrated and the residue was dissolved in water. The aqueous phase was extracted with EA (3 x 60 mL). The combined the organic phases washed with saturated brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc ( EtOAc:EtOAc ) ¹ H-NMR (CDCl ₃ , 400 MHz), δ = 8.10 (s, 1H), 7.29-7.34 (m, 10H), 6.77 (d, J = 8.0 Hz, 4H), 6.36 (d, J = 5.2 Hz, 1H), 5.36 (d, J = 3.6 Hz, 1H), 5.44 (t, J = 4.0 Hz, 1H), 5.32 (d, J = 8.0 Hz, 1H), 3.80 (s, 6H), 3.58 (d, J = 12.8 Hz, 1H), 3.44 (d, J = 12.8 Hz, 1H), 3.29 (s, 2H), 2.10 (s, 3H), 1.82 (s, 3H).

DMAP (178.17 mg, 1.46 mmol) and TPSCl (430.01 mg, 1.46 mmol) were added in one portion to a solution of 297-13 (500 mg, 729.2 μmol) in MeCN (10 mL). 3 hours. NH ₃ /THF (20 mL, sat.) was added, and the mixture was stirred for 1 hour. The mixture was diluted with EA and washed with water. The combined the organic phases washed with saturated brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM: MeOH = 50: 1 ) purified, followed by prep _{HPLC (CH 3 CN / H 2} O) to afford a yellow solid of 297-14 (260mg, 49.5%). ¹ H-NMR (MeOD, 400MHz), δ = 7.60 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.28-7.36 (m, 7H), 6.89 (d, J = 8.4 Hz, 4H), 6.44 (d, J = 4.8 Hz, 1H), 5.56-5.69 (m, 4H), 3.80 (s, 6H), 3.54 (d, J = 13.2 Hz, 1H), 3.39-3.46 (m, 4H), 2.17 (s, 3H), 1.83 (s, 3H).

Was stirred at rt 297-14 (440mg, 642.6μmol) in _{NH 3: MeOH (5mL, 7N} ) in the solution 16 hours. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure at 40 °C. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc : ¹ H-NMR (MeOD, 400MHz), δ = 7.62 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.23 - 7.33 (m, 7H), 6.86 (d, J = 8.4 Hz, 4H), 6.31 (d, J = 4.8 Hz, 1H), 5.54 (d, J = 7.2 Hz, 1H), 4.34 (t, J = 4.4 Hz, 1H), 4.27 (d, J = 4.0) Hz, 1H), 3.78 (s, 6H), 3.69 (d, J = 12.8 Hz, 1H), 3.46 (d, J = 12.8 Hz, 1H), 3.41 (s, 2H).

A solution of 297-15 (150 mg, 249.74 μmol) in 80% CH ₃ COOH (5 mL) was stirred at 60 ° C for 2 hr. TLC showed the reaction was complete. The mixture was treated with MeOH and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc ESI-MS: m/z 299.1 [M+H] ⁺ .

Example 175

At 0 deg.] C, under N _2, over a period 30 minutes, a solution of pyridine was added DMTrCl in portions (100 mL) in the direction 298-1 (12g, 45.42mmol) (16.16g , 47.69mmol) and the mixture was warmed to Stir at 25 ° C for 16 hours. LCMS and TLC (DCM: MeOH = 20:1) eluted starting material. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc :

To a solution of DMTr-298-1 (30.00 g, 52.95 mmol) and TBSCl (19.95 g, 132.38 mmol, 2.50 eq.) in DCM (200 mL) 2.50 equivalents). The temperature is maintained below 5 °C. The mixture was warmed to 25 ° C and stirred for 16 hours. TLC (PE: EA = 1:1) showed the starting material was consumed. The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic phases were washed with brine (50mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated under low pressure. The residue was purified by EtOAc EtOAcqqqqq

The product from the previous step (30.00 g, 44.07 mmol) was dissolved in 80% aqueous AcOH (300 mL) and the mixture was stirred at 25 ° C for 16 hours. TLC (DCM: MeOH = 10:1) showed the reaction was completed. With saturated aqueous NaHCO ₃ (100mL) The reaction was quenched, followed by extraction with EA (3 × 100mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc :

At 25 ℃, under N _2, was added in the IBX to 298-2 (8.00g, 21.14mmol) in MeCN (80mL) solution of (6.51g, 23.25mmol, 1.10 eq). The mixture was heated to 81 ° C for 1 hour. LCMS showed the starting material was consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The aldehyde residue (7.50 g, 19.92 mmol) was used in the next step without further purification.

A solution of 2.0 N aqueous NaOH (19.5 mL) was added in one portion to a solution of aldehyde (7.5 g, 19.9 mmol) from EtOAc (EtOAc) (EtOAc) The mixture was stirred at 25 ° C for 16 hours. TLC showed the reaction was complete. The mixture was cooled to 0 ° C and then neutralized with AcOH to pH = 7. At 0 ℃, solution was treated with NaBH ₄ (4.52g, 119.52mmol). The mixture was stirred for 30 minutes at 25 ℃, and washed with saturated aqueous NH ₄ Cl (100mL) The reaction was quenched. The mixture was extracted with EA (2 x 100 mL). Dried over anhydrous Na ₂ SO ₄ the organic phase was dried, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc:EtOAc

A solution of MMTrCl (3.48 g, 10.28 mmol) in DCM (20 mL) was added dropwise to a solution of 298-3 (4.00 g, 9.79 mmol) in pyridine (20 mL). The temperature is maintained below 5 °C. The mixture was warmed to 25 ° C and stirred at 25 ° C for 16 hours. TLC (DCM: MeOH = 10:1) showed the starting material was consumed. The reaction was quenched with EtOAc (EtOAc) The residue was purified with EtOAc EtOAc m.

To a solution of the above intermediate (5.00 g, 7.03 mmol) and AgNO ₃ (2.39 g, 14.06 mmol, 2.00 eq.) in pyridine (40 mL) was added dropwise TBDPSCl (2.90 g) at 0 ° C. , 10.55mmol). The mixture was warmed to 25 ° C and stirred for 16 hours. TLC (PE: EA = 1:1) showed the starting material was consumed. The reaction was quenched with ice then extracted with EtOAc EtOAc. The combined organic phases were washed with saturated brine (2 × 50mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue (5.00 g, crude) was dissolved in EtOAc (EtOAc) TLC (PE: EA = 2: 1) showed the reaction was completed. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic phase was washed with brine, dried over anhydrous MgSO _4, and concentrated under low pressure. The residue was purified by EtOAc ( EtOAc: EtOAc = EtOAc )

At 0 ℃, under N _2, was added DMP (393.4mg, 927.54μmol, 1.50 equiv) was added to the medium (400mg, 618.36μmol) in DCM (4mL) solution of 298-4 in one portion. The mixture was stirred at 25 ° C for 2 hours. TLC (PE: EA = 2: 1) showed the reaction was completed. The mixture was cooled to 0 ℃ and treated with an aqueous solution (5ml) and saturated Na ₂ SO ₃ aq NaHCO ₃ (5ml) and quenched. The aqueous layer was extracted with DCM (3×10 mL). The combined organic phases were washed with the (10 mL) with saturated brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc: EtOAc :EtOAc

At 0 ℃, under N _2, in pyridine (5mL) in a solution of hydroxylamine hydrochloride was added in one portion to 298-5 (500mg, 775.37μmol) (215.5mg , 3.10mmol, 4.00 equiv). The mixture was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:

TEA (208.0 mg, 2.06 mmol) and MsCl (156.0 mg, 1.36 mmol) were added in one portion to a solution of EtOAc (EtOAc). The mixture was stirred at 25 ° C for 4 hours. TLC (PE: EA = 2: 1) showed the reaction was completed. By saturated aqueous NaHCO ₃ (5ml) The reaction was quenched and extracted with DCM (2 × 20mL) aqueous phase. The combined organic phases were washed with the (10 mL) with saturated brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc ( EtOAc:EtOAc )

To a solution of 298-6 (450.0 mg, 701.10 μmol), DMAP (171.3 mg, 1.40 mmol) and TEA (212.8 mg, 2.10 mmol) in MeCN (5 mL) was added 2, 4 at 0 ° C, 6-Triisopropylbenzene-1-sulfonium chloride (424.7 mg, 1.40 mmol). The mixture was stirred at 25 ° C for 1 hour. TLC (PE: EA = 2: 1) showed the reaction was completed. The reaction was purified by saturated aqueous NaHCO ₃ (5ml) was quenched and extracted with EA (2 × 15mL). The combined organic phases were washed with the (10 mL) with saturated brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue (580.00 mg, 638.59 μmol) was dissolved in MeCN (5 mL). The solution was treated once with NH ₃ ̇H ₂ O (10 mL) at 25 °C. The mixture was stirred at 25 ° C for 16 hours. TLC (PE: EA = 1:1) showed the reaction was completed. The mixture was extracted with EA (3×10 mL). The combined organic phases were washed with the (10 mL) with saturated brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc: EtOAc :EtOAc

NH ₄ F (405 mg, 10.9 mmol) was added in one portion to a solution of 298-7 (350.0 mg, 546.13 μmol) in MeOH (10 mL). The mixture was heated to 65 ° C and stirred for 2 hours. TLC (EA: MeOH = 8:1) showed the reaction was completed. The mixture was cooled to 25 ° C and concentrated under reduced pressure at 40 ° C. By silica gel chromatography (100-200 mesh silica gel, EA: MeOH = 20: 1 to 10: 1) to give the residue obtained as a white solid of 298. ¹ H NMR (400 MHz, DMSO- d ₆ ), δ = 7.59 (d, J = 7.28 Hz, 1H), 7.49 (br.s., 2H), 7.25 (br.s., 1H), 6.29 (br. s., 1H), 6.01 (br.s., 1H), 5.82 (d, J = 7.53 Hz, 1H), 4.60 (br.s., 1H), 3.88 (br.s., 2H); ¹⁹ F _{NMR (376MHz, DMSO- d 6)} d ppm-116.61 (br.s., 1F) -115.98 (br.s., 1F).

Example 176

Add 1-dimethoxy to a solution of K ₂ CO ₃ (967.5 mg, 7.0 mmol) and TsN ₃ (552.2 mg, 2.80 mmol) in MeCN (10 mL) at 25 ° C under N ₂ Phosphonyl propan-2-one (465.1 mg, 2.80 mmol). The mixture was stirred at 25 ° C for 2 hours. At 25 ℃, under N _2, was added in one 298-5 (900.0mg, 1.40mmol, 1.00 eq) of in MeOH (10mL) was added. The mixture was stirred at 25 ° C for 12 hours. TLC (PE: EA = 2: 1) showed the reaction was completed. The mixture was poured into water (10 mL) and extracted with EtOAc EtOAc. The combined organic phases were washed with the (10 mL) with saturated brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc ( EtOAc: EtOAc:EtOAc:EtOAc

₂ was added to a solution of 299.1 (500 mg, 780.20 μmol), DMAP (190.6 mg, 1.56 mmol) and TEA (236.9 mg, 2.34 mmol) in MeCN (5 mL) at 0 ° C. 4,6-Triisopropylbenzene-1-sulfonium chloride (472.8 mg, 1.56 mmol). The mixture was stirred at 0 ° C for 30 minutes, then warmed to 25 ° C and stirred for 2 hours. TLC (PE: EA = 2: 1) showed the reaction was completed. The reaction was quenched with water (5 mL)EtOAc The combined the organic phases are washed with aqueous HCl (1mL, 0.5M), dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. A residue (650.0 mg, 91.83%) was obtained eluted elute

NH ₃ ̇H ₂ O (5 mL) was added in one portion to a solution of the residue (650 mg, 716.4 μmol) from MeCN (5 mL) at 25 ° C, and the mixture was stirred at 25 ° C for 16 hours. TLC (DCM: MeOH = 20:1) showed the reaction was completed. The mixture was extracted with EA (2 x 20 mL). The combined organic phases were washed with brine (10mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc)

A mixture of 299-2 (350.0 mg, 546.98 μmol) and NH ₄ F (405.0 mg, 10.93 mmol) in MeOH (5 mL) was warmed to 65 ° C and stirred for 2 hr. LCMS and TLC (EA: MeOH = 10:1) showed that the reaction was completed. The mixture was cooled to 25 &lt;0&gt;C and filtered and the filtrate was concentrated in vacuo. By silica gel chromatography (300-400 mesh silica gel, EA: MeOH = 20: 1 to 10: 1) to afford a white solid was obtained of 299 (102mg, 64.93%). ¹ H-NMR (400 MHz, METHANOL- d ₄ ), δ = 7.73 (d, J = 7.28 Hz, 1 H), 6.31-6.42 (m, 1 H), 5.95 (d, J = 7.53 Hz, 1 H) , 4.47 (t, J = 13.55 Hz, 1 H), 3.92 (d, J = 12.55 Hz, 1 H), 3.73-3.80 (m, 1 H) 3.25 (s, 1 H); ¹⁹ F NMR (376 MHz, METHANOL- d ₄ ), δ=-115.52--112.60 (m, 1 F).

Example 177

Compound 300

At 0 ℃, under N _2, (20g, 66.8mmol) was added BzCl (30.9g, 220.3mmol) to 300-1 in anhydrous pyridine (180 mL of) in the solution. The mixture was stirred at 25 ° C for 12 hours. The mixture was diluted with EA, and washed with saturated aqueous NaHCO _3. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered, and the filtrate was concentrated to dryness. By silica gel column chromatography (30% EA of containing PE) was obtained residue was purified 300-2 (34.6g, 90%) of a white solid.

The 300-2 (33g, 57.3mmol) was dissolved in 90% CH ₃ COOH (360mL) and heated to 115 ℃. The mixture was stirred at 115 ° C for 12 hours. The solvent was removed and the residue was diluted with EA. The mixture was washed with saturated aqueous NaHCO ₃ and brine. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The filtrate was concentrated to give 300-3 (26 g, crude).

The 300-3 (21g, 44.5mmol) was dissolved in NH ₃ in MeOH solution of (400mL, 10M) in. The mixture was stirred at 25 ° C for 12 hours. The mixture was concentrated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal ¹ H-NMR (CD ₃ OD, 400 MHz) δ = 7.90-7.80 (m, 1H), 6.18-6.09 (m, 1H), 5.71 (d, J = 8.2 Hz, 1H), 4.26 (dt, J = 8.2) , 12.0 Hz, 1H), 3.98-3.84 (m, 2H), 3.76 (dd, J = 2.8, 12.5 Hz, 1H), 3.33 (s, 1H).

At 25 ℃, under N _2, to 300-4 (9g, 34.1mmol) was added TBSCl (7.7g, 51.1mmol) in anhydrous pyridine (60 mL) in the solution. The solution was stirred at 50 ° C for 12 hours. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EA. The mixture was washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried with MgSO ₄ The residue was purified on a silica gel column ( EtOAc EtOAc )

At 25 ℃, under N _2, (, 27mmol 10.2g) in the solution was CH ₂ Cl ₂ (100mL) was added AgNO ₃ (9.2g, 53.9mmol) to 300-5, trimethyl-pyridine (13.1 g of , 107.8 mmol) and MMTrCl (10 g, 32.3 mmol). The solution was stirred at 25 ° C for 12 hours. The reaction was quenched with MeOH and the mixture was filtered on EtOAc. The filtrate was diluted with CH ₂ Cl ₂ and H ₂ O. The organic layer was separated, and extracted with CH ₂ Cl ₂ aqueous phase. The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc )

300-6 (10.5 g, 16.1 mmol) was dissolved in a solution of TBAF in THF (1M, 60 mL). The mixture was stirred at 25 ° C for 4 hours. The mixture was extracted with EA and the combined layers were washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give a crude material which was purified eluting with EtOAc EtOAc EtOAc

At 25 ℃, (17.0g, 31.7mmol) in CH IBX added to 300-7 in the ₃ CN (150mL) solution of (9.7g, 34.9mmol). The mixture was heated to 100 ° C and the mixture was stirred at 100 ° C for 1 hour. The mixture was cooled to 25 °C. The mixture was filtered and the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure to give crystallite crystallite crystal The residue (16 g, crude) was dissolved in 1,4-diosane (150 <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; . The mixture was stirred at 25 ° C for 12 hours. Add EtOH (30mL) at 0 ℃ and NaBH ₄ (10g, 265.7mmol). After stirring at 25 ℃ 1 hour, at 0 ℃ with saturated aqueous NH ₄ Cl The reaction was quenched. The mixture was diluted with EA. The organic phase was separated and the aqueous phase was extracted with EA. Washed with brine the combined organic phase was dried over anhydrous Na ₂ SO _4. The organic layer was concentrated with EtOAc EtOAc m . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=11.52 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.46-7.22 (m, 13H), 6.90 (d, J = 8.8 Hz) , 2H), 6.30 (t, J = 8.0 Hz, 1H), 5.61 (d, J = 8.2 Hz, 1H), 5.06 (t, J = 5.5 Hz, 1H), 4.92-4.86 (m, 1H), 4.61 -4.51 (m, 1H), 3.83 (dd, J = 5.1, 12.1 Hz, 1H), 3.74 (s, 3H).

To 300-8 (2.5g, 4.4mmol) in dry the CH ₂ Cl ₂ (35mL) was added dropwise solution of pyridine (3.5g, 44.1mmol) and _{Tf 2 O (3.7g, 13.2mmol)} . The mixture was stirred at 0 ° C for 40 minutes. The reaction was quenched with ice water and stirred for 10 min. The mixture was extracted with CH ₂ Cl ₂ . Dried over MgSO ₄ and the organic layer was washed with brine. The organic layer was concentrated to give a crystal crystal crystal crystal crystal crystal crystal crystals

At 0 ℃, under N _2, was added NaH (107mg, 2.7mmol) was stirred in to the 300-9 (1.8g, 2.2mmol) in dry DMF (25mL) solution via. The solution was stirred at 25 ° C for 1 hour. TLC (PE: EA = 1:1) showed the reaction was completed. NaI (3.1 g, 20.6 mmol) was added to the solution at 25 °C. The mixture was stirred at 25 ° C for 3 hours. TLC (PE: EA = 1:1) showed the reaction was completed. The mixture was diluted with water and extracted with EA. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The filtrate was concentrated under reduced pressure to afford 300-10 (1.4 g, crude)

300-10 (1.4 g, crude product) was dissolved in 1,4-dioxane (25 mL), and the mixture was treated with aqueous NaOH (2M, 2.7 mL). The solution was stirred at 25 ° C for 4 hours. With saturated aqueous NH ₄ Cl The reaction was quenched and extracted with EA. The organic layer was washed with brine. The organic layer was filtered and was dried over anhydrous Na ₂ SO _4. The filtrate was concentrated to give a crude material, which was purified by EtOAc EtOAc ( EtOAc )

In the solution was added Et ₃ N (434mg, 4.3mmol) and Pd / C (101mg, 88.7μmol) to 300-11 (1.45g, 2.1mmol) in EtOH (10mL). The mixture was stirred at H ₂ (15 psi) for 12 hours at 25 °C. The suspension was filtered and the filtrate was concentrated at low pressure. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc )

At 25 ℃, under N _2, to 300-12 (930mg, 1.7mmol) in dry (10 mL) in of DMF was added imidazole (287mg, 4.2mmol) and TBSCl (636mg, 4.2mmol). The solution was stirred at 25 ° C for 5 hours. The mixture was concentrated to dryness under reduced pressure and the residue was dissolved in EA. The mixture was washed with a saturated aqueous solution of NH ₄ Cl and brine. The organic layer was dried over MgSO _4, and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was purified on a EtOAc EtOAc EtOAc ( EtOAc )

At 25 ℃, to 300-13 (568mg, 854.4μmol) in dry CH added DMAP (209mg, 1.7mmol) in the ₃ CN (8mL) was stirred in, TPSCl (504mg, 1.7mmol) and TEA (173mg, 1.7 mmol). The mixture was stirred at 25 ° C for 12 hours. NH ₃ ̇H ₂ O (10 mL) was added, and the mixture was stirred for 3 hr. The mixture was extracted with EA and washed with saturated aqueous NH ₄ Cl and with brine. The organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 7.65-7.40 (m, 13H), 6.97 (d, J = 8.8 Hz, 2H), 6.44 (dd, J = 6.4, 9.5 Hz, 1H), 5.71 (d) , J = 7.3 Hz, 1H), 4.76 (dd, J = 9.0, 14.4 Hz, 1H), 4.29 (q, J = 7.1 Hz, 1H), 3.92-3.92 (m, 1H), 3.95 (s, 3H) , 3.60 (d, J = 11.2 Hz, 1H), 3.44 (d, J = 11.0 Hz, 1H), 1.66-1.55 (m, 3H), 0.95 (s, 9H), 0.08 (s, 3H), 0.00 ( s, 3H).

300-14 (501 mg, 753.2 μmol) was dissolved in 80% HCOOH (20 mL), and the mixture was stirred at 25 ° C for 4 hours. A low pressure solvent was removed, and the residue was purified on a silica gel column (6% MeOH containing of DCM) was obtained as a white solid of 300 (151mg, 71.8%). ESI-MS: m/z 278.11 [M+H] ⁺ , 555.18 [2M+H] ⁺ .

Example 178

To a solution of 301-1 (120 g, 0.26 mol) in anhydrous MeCN (2 L) was added IBX (109 g, 0.39 mol). The mixture was heated to reflux and stirred for 18 hours. The mixture was cooled to 0 ° C and filtered. The filtrate was concentrated in vacuo to obtain a brown oil of 301-2 (142g), which was used without purification in the next step.

To a solution of 301-2 (142 g) in dry THF (1.5 L) was added dropwise ethyl magnesium bromide (830 mL, 0.83 mol, 1 N) at -78 ° C, and the mixture was stirred at -78 ° C. hour. At 0 ℃, by saturated aqueous NH ₄ Cl (2L) The reaction was quenched. The THF was removed in vacuo and the residue was diluted with EtOAc. Solution was washed with brine, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a pale brown oil.

DMAP (63.5 g, 0.52 mol), Et ₃ N (79 g, 0.78 mol) and BzCl (110 g, 0.78 mol) were added to dry DCM (2.5 L). The mixture was stirred overnight at room temperature. The mixture was diluted with DCM (2L) and washed with saturated aqueous NaHCO ₃ (3L) and washed (1.5 L of) brine. The organic phase was dried over anhydrous Na ₂ SO _4, filtered and evaporated to dryness under reduced pressure. By silica gel column (PE: EA = 20: 1 to 10: 1) was obtained residue was purified 301-3 (112.7g, 72.3%) of a yellow oil.

The mixture of uracil (36.25 g, 323.7 mmol) and N,O-bis(trimethyldecyl)acetamide (131.69 g, 647.4 mmol) in anhydrous MeCN (180 mL) Cool to room temperature. In the Add 301-3 (95.9g, 161.85mmol) in dry MeCN (500mL) was followed by SnCl ₄ (168.66g, 647.4mmol) was treated with dropwise at 0 ℃. The mixture was heated to reflux and stirred for 2 hours. The reaction was quenched with saturated aqueous NaHCO ₃ (3L) and extracted with EtOAc (3 × 1L). The organic phase was washed with brine (500mL), dried over anhydrous Na ₂ SO _4, filtered and evaporated to dryness under reduced pressure. The residue was purified by EtOAc ( EtOAc: EtOAc = EtOAc )

The 301-4 (33g, 56.65mmol) was dissolved in NH _3: in MeOH (800mL, 7N), and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was purified mjjjjjjjjjjjjjj

Was added AgNO ₃ (8.93g, 52.56mmol) and imidazole (3.58g, 52.56mmol) to 301-5 (2.57g, 8.76mmol) in DMF (20mL) in the solution, followed at 0 deg.] C, under N ₂ TBSCl (5.28 g, 35.04 mmol) was added in one portion. The mixture was stirred at 25 ° C for 12 hours. TLC showed the reaction was complete. The residue was poured into ice: water (w: w = 1:1) (30 mL). The aqueous phase was extracted with EA (3 x 100 mL). The combined organic phases were washed with saturated brine (3 × 20mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE: EA = 3:1 to 2:1) to afford 301-6 (3.68 g, 80.51%).

To a solution of 301-6 (3.48 g, 6.67 mmol) and AgNO ₃ (3.40 g, 20.01 mmol) in pyridine (30 mL) at 25 ° C under N ₂ (chloro (4-methoxy) Phenylphenyl)methylene)diphenyl (4.12 g, 13.34 mmol). The mixture was stirred at 25 ° C for 16 hours. TLC showed the reaction was complete. The mixture was diluted with EA and filtered. The filtrate was washed with brine and separated. The organic layer was concentrated to dryness. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE: EA = 10:1 to 5:1) to obtain 301-7 (4.40 g, as a yellow foam. 83.07%).

NH ₄ F (801.55 mg, 21.64 mmol) was added in one portion to a solution of 301-7 (4.30 g, 5.41 mmol) in MeOH (100 mL). The mixture was heated to 68 ° C and stirred for 4 hours. The LCMS trace shows the completion of the reaction. The mixture was cooled to 25 ° C and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silicone, DCM: MeOH: NH ₃ .H ₂ O = 30:1:0.05 to 10:1:0.05). 301-8 (3.00 g, 98.04%) as a white solid.

At 0 ℃, under N _2, was added in one NaH (848mg, 21.20mmol) to 301-8 (3.00g, 5.30mmol) in the in DMF (30mL) solution. The mixture was stirred at 0 ° C for 30 minutes. BnBr (3.63 g, 21.20 mmol) was added at 0 ° C, and the mixture was stirred at 25 ° C for 16 hours. TLC showed the reaction was complete. The mixture was poured into ice-water (w/w = 1/1) (30 mL). The aqueous phase was extracted with EA (3 x 50 mL). The combined organic phases were washed with saturated brine (3 × 20mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 200-300 mesh silica gel, PE: EA = 20:1 to 10:1) to obtain 301-9 (670 mg, 15.1%).

Ozone was bubbled into a solution of 301-9 (500 mg, 598.10 μmol) in DCM (8 mL) and MeOH (8 mL) at -78 °C for 20 min. After purging excess O ₃ by O ₂ , NaBH ₄ (113.13 mg, 2.99 mmol) was added at 0 °C. The mixture was stirred at 25 ° C for 20 minutes. TLC showed the starting material was consumed. The mixture was concentrated to give EtOAc (EtOAc: EtOAc)

At 0 ℃, under N _2, to 301-10 (216.70mg, 257.99μmol) and DMAP (63.04mg, 515.98μmol) in DCM (2mL) was added in one portion a solution of the MsCl (44.33mg, 386.98μmol) . The mixture was stirred at 0 ° C for 1 hour, then warmed to 25 ° C and stirred for 1 hour. LCMS showed the reaction was completed. The residue was poured into ice-water (w/w = 1 / 1) (10 mL) The combined organic phases were washed with saturated brine (3 × 10mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE: EA = 10:1 to 5:1) to obtain a methanesulfonated intermediate in the form of a yellow foam (167.00 Mg, 70.51%).

The mesylate intermediate (167 mg) was dissolved in TBAF: THF (10 mL, 1 N) and the mixture was warmed to reflux for 12h. The mixture was slowly cooled to 25 ° C and quenched with a saturated solution of NH ₄ Cl. The solution was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ dried and concentrated to dryness. The residue was purified by column chromatography ( EtOAc: EtOAc: EtOAc: EtOAc )

301-11 (80.00 mg, 0.087 mmol) was dissolved in 80% AcOH solution (5 ml) and stirred at 45 ° C for 1.0 hour. The reaction was quenched with a saturated solution of Na ₂ HCO ₃ and extracted with EA (3 × 10mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ dried and concentrated to dryness. The residue was purified by column chromatography to afford 301 < RTIgt; ESI-MS: m/z 570.4 [M+H] ⁺ .

Was added BCl ₃ /DCM(1.0N)(1mL) to (0.5mL) in a solution of 301-12 (113.8mg, 0.2mmol) in DCM at -78 ℃, and the mixture was stirred at -78 ℃ 30 minutes. The reaction was quenched with MeOH and concentrated to dryness. By prep HPLC (with NH ₃ ˙H ₂ O buffer) to give a white solid was obtained of 301 (26mg, 44%).

Example 179

At 0 ℃, under N _2, was added BzCl (496mg, 3.5mmol) to 302-1 (2.00g, 3.5mmol) in pyridine (10 mL) and DCM (10mL) in the mixture was added dropwise. The mixture was stirred at 0 ° C for 30 minutes, followed by stirring at 25 ° C for 6.5 hours. With saturated aqueous NaHCO ₃ (80 mL) The reaction was quenched. The mixture was extracted with EA (2 x 100 mL). The organic phase was washed with brine (80mL), dried over anhydrous Na ₂ SO ₄ dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

At 25 ℃, under N _2, was added to a mixture of imidazole (5mL) in the 302-2 (680mg, 1.0mmol) in DMF _{(412mg, 6.1mmol), AgNO 3} (514mg, 3.0mmol) and TBDPSCl (832mg , 3.0 mmol). The mixture was stirred at 25 ° C for 12 hours. The reaction was quenched with saturated aqueous NaHCO ₃ (30mL), then extracted with EA (2 × 30mL). The combined organic phases were washed with brine of (2 × 20mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc )

The 302-3 (660mg, 0.7mmol) was dissolved in NH _3: MeOH (15mL) in. The mixture was stirred in a sealed tube at 25 ° C for 36 hours, then concentrated under reduced pressure. The residue was purified by EtOAc EtOAc ( EtOAc ) ¹ H-NMR (CDCl ₃ , 400 MHz) δ=9.05 (s, 1H), 7.81-7.10 (m, 21H), 6.81 (d, J = 9.2 Hz, 2H), 6.42 (m, 1H), 6.20 (m) , 1H), 4.13-4.07 (m, 2H), 3.78-3.60 (m, 5H), 2.55 (s, 1H), 0.90-0.74 (m, 9H).

At 0 ℃, under N _2, To a solution of 302-4 (280mg, 0.3mmol) of DCM (3.5mL) was added in one portion in the mixture of Dess - Martin (295mg, 0.7mmol). The mixture was stirred at 25 ° C for 3.5 hours. With saturated aqueous NaHCO ₃ and Na ₂ S ₂ O ₃ saturated aqueous (v: v = 1: 1,30mL ) The reaction was quenched. The mixture was extracted with EA (2 x 20 mL). The combined organic phases were washed with brine (30mL), dried over anhydrous Na ₂ SO ₄ dried and filtered. The filtrate was concentrated in vacuo to obtain a yellow solid of 302-5 (260mg, crude), which was used without further purification in the next step.

Add KOBu-t (1 mL, 1.0 mmol, 1 M in THF) dropwise to a stirred solution of methyl-triphenyl-hydrazine bromide (359 mg, 1.0 mmol) in anhydrous THF (1 mL) . The mixture was stirred at 25 ° C for 1 hour. A solution of 302-5 (260 mg, 0.3 mmol) in dry THF (1 mL) was obtained. The mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (20mL) and extracted with EA (30mL). The organic layer (20mL) and washed with brine, dried over MgSO _4, filtered and evaporated to obtain pale white solid, which by column chromatography (10% EA of containing PE) to afford a yellow solid of 302-6 (131mg, 50%). ¹ H-NMR (CDCl ₃ , 400 MHz) δ=8.40 (s, 1H), 7.55-7.21 (m, 21H), 7.10 (dd, J = 1.8, 8.2 Hz, 1H), 6.84 (d, J = 8.8 Hz) , 2H), 6.37 (dd, J = 11.0, 17.4 Hz, 1H), 6.09 (dd, J = 7.2, 8.9 Hz, 1H), 5.59-5.43 (m, 2H), 5.10-4.92 (m, 2H), 3.85-3.78(s,3H), 3.78-3.73 (m,1H), 3.56 (d, J = 11.5 Hz, 1H), 0.99-0.77 (s, 9H).

At 27 ℃, under N _2, was added to 9-BBN in the 302-6 (1.50g, 1.9mmol) in THF (5mL) solution (0.5M, 22.5mL). The mixture was heated to 70 ° C by microwave and stirred for 0.5 hours. A saturated aqueous solution of NaHCO ₃ (15 mL) and H ₂ O ₂ (7.5 mL) were then weighed. The mixture was vigorously stirred at 27 ° C for 1.5 hours. With saturated aqueous _{Na 2 S 2 O 3 (60mL} ) The reaction was quenched. The mixture was extracted with EA (2 x 50 mL). The organic layer was washed with brine (80mL), dried over MgSO _4, filtered and evaporated to dryness. The residue was purified by EtOAc EtOAc ( EtOAc )

At 0 ℃, under N _2, was added to the Dess of (1.24g, 1.5mmol) in DCM (15mL) solution in one portion 302-7 - Martin (1.28g, 3.0mmol). The mixture was stirred at 27 ° C for 2 hours. With saturated aqueous NaHCO ₃ and Na ₂ S ₂ O ₃ saturated aqueous (v: v = 1: 1,60mL ) The reaction was quenched. The mixture was extracted with EA (2 x 50 mL). Washed with brine (80 mL) the organic layers were combined, dried over anhydrous Na ₂ SO ₄ dried and filtered. The filtrate was concentrated in vacuo to obtain a yellow solid of 302-8 (1.21g, crude).

To a stirred solution of methyl-triphenyl-phosphonium bromide (1.64 g, 4.6 mmol) in EtOAc (EtOAc) The mixture was stirred at 27 ° C for 1 hour. A solution of 302-8 (1.21 g of crude product, 1.5 mmol) in THF (5 mL). The mixture was stirred at 27 ° C for 12 hours. The reaction was quenched with aqueous saturated NH ₄ Cl (70mL), extracted with EA (2 × 50mL). The organic layer was washed with brine (80 mL), dried over MgSO _4, filtered and evaporated to dryness to give a light yellow solid was obtained which was purified by column chromatography (15% EA of containing PE) of 302-9 as a white solid ( 970 mg, 80%).

At 27 ℃, under N _2, (, 1.2mmol 970mg) in the in CH ₃ CN (10mL) was added TPSCl (877mg, 3.0mmol) to 302-9, DMAP (363mg, 3.0mmol) and TEA ( 301 mg, 3.0 mmol). The mixture was stirred at 27 ° C for 1.5 hours. NH ₃ ̇H ₂ O (5 ml) was added, and the reaction mixture was stirred at 27 ° C for 2 hr. The reaction was quenched with aqueous saturated NH ₄ Cl (60mL), then extracted with EA (2 × 40mL). The combined organic phases were washed with brine (60mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc :EtOAc

At 27 ℃, under N _2, was added NH ₄ F (455mg, 12.3mmol) in to the 302-10 (500mg, 0.6mmol) in MeOH (15mL) solution. The mixture was stirred at 70 ° C for 12 hours. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. By silica gel chromatography (5% MeOH in the DCM) to obtain the crude product The residue was purified 302 (120mg, crude). By preparative HPLC (neutral conditions) to give the crude product was obtained as a white solid of 302 (86mg, 45%). MS: m/z = 304 [M + H] ⁺ .

Example 180

TsOH was added in one portion to a mixture of 303-1 (30 g, 122.85 mmol) and 1,1-dimethoxycyclopentane (86 g, 660.93 mmol) in DCE (200 mL). H ₂ O (2.34 g, 12.29 mmol). The mixture was heated to 70 ° C and stirred for 14 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc ( EtOAc

At room temperature to 303-2 (20g, 64.45mmol) in dry CH of the ₃ CN (200mL) was added IBX (19.85g, 70.9mmol). The mixture was refluxed for 18 hours and then cooled to 0 °C. The precipitate was filtered off, and the filtrate was concentrated to obtain a yellow solid of the crude product 303-3 (20g, 100%).

To a solution of 303-3 (20 g, 64.87 mmol) in 1,4-dioxane (200 mL), EtOAc (EtOAc) The mixture was stirred at room temperature overnight, then neutralized with AcOH to pH = 7. At 20 ℃ solution was treated with NaBH ₄ (4.91g, 129.74mmol). The mixture was stirred at room temperature for 1 hour. With saturated aqueous NH ₄ Cl The reaction was quenched. The mixture was extracted with EA (3 x 100 mL). Na ₂ SO ₄ organic layers were dried over anhydrous, low-pressure concentrated. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc

At -30 ℃, to 303-4 (15.50g, 45.54mmol) in anhydrous pyridine (80.00mL) was added dropwise in the solution containing DMTrCl (18.52g, 54.65mmol) of anhydrous DCM (20.00mL). The mixture was stirred at 25 ° C overnight. The solution was treated with MeOH and concentrated at low pressure. By column chromatography (50% EA of containing PE) Purification of the residue obtained as a yellow solid of 303-5 (10.59g, 32.56% yield).

Added to in the AgNO ₂ Cl _{2 (20.00mL)} was 303-5 (2.90g, 4.51mmol) in CH of ₃ (1.15g, 6.77mmol), imidazole (767.60mg, 11.28mmol) and TBDPSCl (1.86g, 6.77 Mm). The mixture was stirred at 25 ° C for 14 hours. The precipitate was filtered off, and the filtrate was washed with water, and dried over anhydrous Na ₂ SO _4. Remove solvent at low pressure. The crude residue was purified by EtOAc (EtOAc:EtOAc)

303-6 (2.79 g, 3.17 mmol) was dissolved in 80% aqueous HOAc (50 mL). The mixture was stirred at 25 ° C for 4 hours. The solution was treated with MeOH and concentrated at low pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc )

At 0 ℃, under N _2, to 303-7 (1.50g, 2.59mmol) in dry DCM (20mL) was added in the Dess - Martin periodinane (1.32g, 3.11mmol). The mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of a saturated aqueous solution of Na ₂ S ₂ O ₃ / sodium bicarbonate. The mixture was stirred for 15 minutes. The organic layer was separated, washed with brine brine and evaporated. The crude residue was purified by EtOAc EtOAc elut elut elut elut elut elut

At -70 ℃, under N _2, (, 4.16mmol 1.49g) in dry THF was added n-BuLi (0.41mL, 3.47mmol) (15mL) in a solution of the PPh ₃ CH ₃ Br. The mixture was stirred at 0 ° C for 0.5 hours. At 0 ℃, under N _2, was added dropwise 303-8 (800.00mg, 1.39mmol) in dry of THF (3mL) was added. The mixture was stirred at 25 ° C for 2 hours. The reaction was quenched with saturated NH ₄ Cl solution, and extracted with EtOAc (3 × 60mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The crude product was purified by EtOAc EtOAc elut elut elut elut elut

At room temperature, was added 2,4,6-triisopropylbenzene sulfonic acyl chloride (526.95mg, 1.74mmol) in to the 303-9 (500mg, 869.96μmol) in dry CH ₃ CN (10.00mL) solution of , DMAP (212.57mg, 1.74mmol) and _{Et 3 N (1.83g, 18.04mmol)} . The mixture was stirred at 25 ° C for 1 hour. NH ₃ ̇H ₂ O (5.00 mL) was added, and the mixture was stirred for 1 hour. The mixture was extracted with EA and washed with brine, 0.1M HCl and saturated NaHCO ₃ solution. The organic phase was dried over anhydrous Na ₂ SO _4, and concentrated under low pressure. By silica gel chromatography (EtOAc) to obtain the residue was purified as a yellow solid of 303-10 (307mg, 55.36%).

At 25 ℃, under N _2, was added to the medium of 303-10 (307mg, 535.08μmol) in MeOH (4mL) solution of _{NH 4 F (814mg, 20mmol)} . The mixture was stirred at 65 ° C for 16 hours. The solution was filtered and evaporated to dryness. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc )

At 25 ℃, under N _2, with HCl: MeOH (6mL, 1N) treated 303-11 (108mg, 322.05μmol). The mixture was stirred at 25 ° C for 1 hour. The aqueous phase was extracted with EA (3×10 mL). The residual aqueous solution was lyophilized to give 303 (yield: 80.00, ESI-MS: m/z 270 [M+H] ⁺ .

Example 181

At 25 ℃, under N _2, to _{K 2 CO 3 (2.40g, 17.35mmol} ) and TsN ₃ (1.37g, 6.94mmol) in the in CH ₃ CN (20mL) was added in one portion a mixture of 1-dimethylamino Oxyphosphonium propan-2-one (1.15 g, 6.94 mmol). The mixture was stirred at 25 ° C for 2 hours. At 25 ℃, under N _2, was added in one 304-1 (2.00g, 3.47mmol) solution (20mL) in the in MeOH, and the mixture was stirred at 25 ℃ 16 h. The mixture was poured into water and extracted with EtOAc (2×30 mL). The organic phase was washed with brine the combined, dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc ( EtOAc )

At 0 ℃, (600mg, 1.05mmol) in of anhydrous CH ₃ CN (60mL) was added to 304-2 TEA (212mg, 2.10mmol), DMAP (256mg, 2.10 mmol) and 2,4,6- Triisopropylbenzenesulfonium chloride (635 mg, 2.10 mmol). The mixture was stirred at 25 ° C for 1 hour. NH ₃ ̇H ₂ O (10 mL) was added at 25 °C. The mixture was stirred at 25 ° C for 1 hour. The reaction was quenched with saturated NH ₄ Cl solution, and extracted with EtOAc (2 × 10mL). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ dried, and concentrated under low pressure. The residue was purified by EtOAc ( EtOAc:EtOAc:EtOAc :

Was stirred at 65 ℃ 304-3 (300mg, 0.52mmol) and NH ₄ F (194mg, 5.25mmol) in dry MeOH (5mL) of the solution 12 hours. Concentrate the mixture at low pressure. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc

A solution of 304-4 (100 mg, 0.30 mmol) in 1N EtOAc MeOH (5 mL). The mixture was concentrated at 40 °C. With CH ₃ CN (5 × 2mL) was obtained as a white residue was washed solid of 304 (61mg, 67%). ESI-LCMS: m/z 268.1 [M+H] ⁺ .

Example 182

To a solution of N- (tert-butoxycarbonyl)-L-proline (8.06 g, 37.1 mmol, 1.5 eq.) in anhydrous ACN (60 mL) EtOAc (EtOAc) . The reaction was stirred at room temperature for 1 hour then cooled to 0 °C. Was added in the 44 (14.9g, 24.7mmol, 1 eq) in anhydrous ACN (50mL) solution was added to a cooled solution of N-BOC- valine of the imidazole, and treated with _{Et 3 N (6.4mL, 49.4mmol,} 2 eq. The resulting solution is treated. The reaction was carried out at 0 ° C for 1 hour. The reaction was quenched with 1M EtOAc EtOAc (EtOAc)EtOAc. The organic layer was separated and washed sequentially with water and semi-saturated sodium hydrogen carbonate and water (2×). The organic layer was concentrated under reduced pressure and the residue was dissolved in EtOAc (EtOAc) The solid was aged at 0&lt;0&gt;C overnight and was isolated by filtration to afford 305-1 (18.0 g, 90.9%) as a white solid. MS: m/z = 802 [M + 1] ⁺ .

A solution of 305-1 (2.4 g, 3 mmol) in IPAC (45 mL) was stirred with methanesulfonic acid (0.39 mL, 6 mmol, 2 eq.) and the mixture was stirred at 40 °C. After 1 hour, methanesulfonic acid (2 x 0.2 mL, 6 mmol, 2 eq.) was added and the temperature was increased to 50 °C. After 5 hours, the mixture was cooled to room temperature. The solid was filtered off, washed with IPAC and dried in vacuo to obtain 305 (2.0g, 83%). Melting point = 146 ° C; MS: m/z 702.2 [M+H] ⁺ .

Example 183 Triphosphate

Anhydrous nucleoside (0.05 mmol) was dissolved in a mixture of PO (OMe) ₃ (0.7 mL) and pyridine (0.3 mL). The mixture was evaporated under vacuum at a bath temperature (42 ° C) for 15 minutes and then cooled to room temperature. N-methylimidazole (0.009 mL, 0.11 mmol) and POCl ₃ (9 μL, 0.11 mmol) were added sequentially, and the mixture was kept at room temperature for 20-40 minutes. The reaction was controlled by LCMS and monitored by the appearance of the corresponding nucleoside 5'-monophosphate. After completion, tetrabutylammonium pyrophosphate (150 mg) was added, followed by DMF (0.5 mL) to obtain a homogeneous solution. After 1.5 hours at ambient temperature, the reaction was diluted with water (10 mL) and loaded onto a column of HiLoad 16/10 with high-purity Q agarose. The separation was carried out in a linear gradient of 0 to 1 N NaCl in 50 mM TRIS buffer (pH 7.5). The triphosphate is dissolved at 75-80% B. Concentrate the corresponding dissolved fraction. Desalting was achieved by RP HPLC on a Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of 0 to 30% methanol in 50 mM triethylammonium acetate buffer (pH 7.5) was used to dissolve. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess buffer. Examples of compounds prepared according to this procedure are provided in Table 2.

Example 184 Compounds of formula (I) and (II)

The foregoing syntheses are exemplary and can be used as a starting point for the preparation of additional compounds of formula (I) and (II). Examples of additional compounds of formula (I) and (II) are shown below. Such compounds can be prepared in a variety of ways, including those synthetic schemes shown and described herein. Those skilled in the art will be able to recognize modifications and alternatives to the disclosed compositions based on the disclosure herein; all such modifications and alternatives are within the scope of the patent application.

Example 185 Picornavirus analysis

The cells were HeLa-OHIO (Sigma-Aldrich, St.Louis, MO ) were seeded at a density of 1.5 × 10 ⁵ cells to the assay medium in 96-well plates (without phenol red free MEM or L- Glutamic acid amide of Supplemented with 1% FBS, 1% penicillin/streptomycin, 2 mM GlutaGro and 1 x MEM non-essential amino acids, all from Cellgro, Manassas, VA). The analysis was set after the cells were allowed to adhere for 24 hours. Compounds dissolved in DMSO were serially diluted in assay medium up to 2 x final concentration. The medium was aspirated from the cells, and 100 μl of the medium having the compound was added in triplicate. Human rhinovirus 1B (ATCC, Manassas, VA) was diluted in assay medium and 100 μL was added to cells and compounds. The selection of the virus inoculum caused an 80-90% cytopathic effect within 4 days. Infected cells were incubated for 4 days at 33 ° C, 5% CO ₂ . For analysis, 100 μL of medium was changed to 100 μL of CellTiter-Glo® reagent (Promega, Madison, WI) and incubated for 10 minutes at room temperature. Luminescence was measured on a Victor X3 multi-label reader.

The compounds of formula (I) and (II) are active in this assay. Exemplary antiviral activity of the compounds shown in Table 3, where "A" indicates EC ₅₀ <1μM, "B" indicates EC ₅₀ 1 μM and <10 μM, and “C” indicates EC ₅₀ 10 μM and <100 μM.

table 3

HeLa-OHIO cells were seeded at a density of 1.5×10 ⁵ cells per ml (1.5×10 ⁴ cells per well) in an assay medium in clear black 96-well plates (MEM without phenol red or L-glutamic acid) (Gibco Cat. No. 51200) supplemented with 1% FBS, 1% penicillin/streptomycin (Mediatech Cat. No. 30-002-CI), and 1% Glutamax (Gibco Cat. No. 35050). After 24 hours, the medium was removed. and replaced with serial dilutions of the compound in the assay medium. EC ₅₀ for measuring the equivalent inoculum cells infected with HRV-1b 100μL of assay medium of 70 TCID ₅₀ or another strain of the virus in different virus inoculum Standardization between strains was performed to achieve a signal/background ratio of 10. After 4-6 days, cell viability was measured using the CellTiter Glo Luminescent Cell Viability Assay (Promega Cat. No. G7572). 100 μL of medium was removed from each well and 100 μL of CellellTiter Glo reagent was added. the plate was incubated at room temperature for 5 minutes, followed by multi-label counter using a Perkin Elmer Victor3V emission measurement. EC ₅₀ values measured using the XLFit.

Compounds 44 and 160 were found to be active and directed against several human rhinovirus strains (including HRV-25, HRV-56, HRV-21, HRV-02, HRV-19, HRV-16, HRV-53, HRV-68, HRV). -45, HRV-84, HRV- 70, HRV-79 and HRV-14) the EC ₅₀ of less than 1μM. HRV-89 for the two compounds are also active, and 160 each compound has an EC 44 in the range of 1μM to 2μM _50. In contrast, BTA-798 (Vapendavir) was found to be inactive against 2 of the 15 tested strains. Furthermore, compounds 44 and 160 were not cytotoxic in the HeLa OHIO host cell line (CC ₅₀ >100 μM (n>5)).

Example 186 MicroRNA virus polymerase inhibition assay

The enzymatic activity of human rhinovirus 16 polymerase (HRV16pol) was measured by incorporating deuterated NMP into the acid insoluble RNA product. The HRV16pol assay reaction contained 30 Nm recombinase, 50 Nm heteropolyRNA, about 0.5 μCi deuterated NTP, 0.1 Mm competition cold NTP, 40 Mm Tris-HCl (Ph 7.0), 3 Mm dithiothreitol, and 0.5 Mm MgCl ₂ . The standard reaction was incubated at 30 ° C for 2.5 hours in the presence of increasing concentrations of inhibitor. At the end of the reaction, RNA was precipitated with 10% TCA and the acid insoluble RNA product was filtered on a size exclusion 96 well plate. After washing the plates, scintillation fluid was added and the radiolabeled RNA product was detected using a Trilux Microbeta scintillation counter according to standard procedures. The data was fitted by nonlinear regression (S-shaped) to calculate the enzymatic rate is reduced by 50% in which the compound concentration (IC _50).

Several independent experiments from an average value of the IC ₅₀ value is derived and shown in Table 4. The compounds of formula (I) and (II) exhibit activity in this assay. The "A" value in the table below indicates IC ₅₀ <1 μM, the value of "B" indicates IC ₅₀ <10 μM, and the value of "C" indicates that the IC ₅₀ value is <100 μM.

Example 187 Enterovirus analysis cell

HeLa OHIO cells were purchased from Sigma Aldrich (St Louis, MO) and cultured in Glutamax MEM (Gibco Cat. No. 41090) at 37 ° C and 5% CO ₂ supplemented with 10% FBS (Mediatech Cat. No. 35-011- CV) and 1% penicillin/streptomycin (Mediatech Cat. No. 30-002-CI). RD cells were purchased from ATCC (Manassas, VA) and cultured in DMEM at 37 ° C and 5% CO ₂ supplemented with 10% FBS (Mediatech catalog number 35-011-CV) and 1% penicillin/streptomycin. (Mediatech catalog number 30-002-CI).

Judging anti-enteric activity

For HRV16, EV68 and CVB3, HeLa-OHIO cells were seeded in assay medium (without phenol red or L) in a clear bottom black 96-well plate at a density of 1.5 x 10 ⁵ cells per ml (1.5 x 10 ⁴ cells per well). - Brassic acid MEM (Gibco Cat. No. 51200) supplemented with 1% FBS, 1% penicillin/streptomycin (Mediatech Cat. No. 30-002-CI), and 1% Glutamax (Gibco Cat. No. 35050). For EV71, RD cells were seeded at a density of 5 x 10 ⁴ cells per ml (5000 cells per well) in assay medium (DMEM supplemented with 2% FBS and 1% penicillin/streptomycin). After 24 hours, the medium was removed and replaced with serial dilutions of the compound in the assay medium. for EC ₅₀ measured cells having sufficient to obtain infected control cells compared to uninfected controls decreased 100μL analysis of cell viability in cells 10-fold virus inoculum medium Infection. After 2-6 days, cell viability was measured using CellTiter Glo Luminescent Cell Viability Assay (Promega Cat. No. G7572). Cells infected with EV-71 and CVB3 were cultured at 37 ° C, and infected with HRV-16 or EV-68. The cells were cultured at 33 ° C. 100 μL of medium was removed from each well and 100 μL of CellT was added. iter Glo reagent assay plates incubated for 5 minutes at room temperature, followed by multi-label counter using a Perkin Elmer Victor3V emission measurement. EC ₅₀ values measured using the XLFit.

Compound EC 44 in the 0.38 to 2.52 m (average 1.39 ± 1.14μM) range of ₅₀ to suppress all four test virus (human rhinovirus 16 (HRV-16), Coxsackievirus B3 (CVB3), enterovirus -68 Replication of (EV-68) and Enterovirus-71 (EV-71). In contrast, BTA-798 was inactive against all tested viruses and was found to be inactive against CVB3. As described herein, Compound 44 can be obtained after removal of a group attached to a phosphorus of a compound described herein (eg, a compound of Formula (I) and/or (II) or a pharmaceutically acceptable salt thereof); Thus, the compound 44 prodrug is also active against the picornaviruses described herein.

Example 188 HCV replicon analysis cell

In Dulbock containing 2 mM L-glutamic acid supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomycin, 1% non-essential amino acid and 0.5 mg/Ml G418 Huh-7 cells containing a self-replicating subgenomic HCV replicon and a stable luciferase (LUC) reporter were cultured in Dulbecco's modified Eagle's medium (DMEM).

Determination of anti-HCV activity

Measured by the following procedure replicon cells in the compound 50% inhibitory concentration (EC ₅₀₎ in HCV. On the first day, 5,000 HCV replicon cells were seeded per well in a 96-well plate. The next day, the test compound was dissolved in 100% DMSO until 100 times the desired final test concentration. Each compound was then serially diluted (1:3) up to 9 different concentrations. The 100% DMSO solution of the compound was reduced to 10% DMSO by dilution 1:10 in cell culture medium. Compounds were diluted to 10% DMSO in cell culture medium for addition to HCV replicon cells in 96 well format. The final DMSO concentration was 1%. HCV replicon cells were incubated at 37 ° C for 72 hours. At 72 hours, the cells were treated while the cells were still confluent. Compounds that reduce LUC signaling were assayed by Bright-Glo Luciferase Assay (Promega, Madison, WI). For each compound concentration was measured to calculate the EC ₅₀ with respect to percent inhibition of control cells (the untreated HCV replicon) of.

The compounds of formula (I) and (II) are active in the HCV replicon assay. Exemplary antiviral activity of the compounds shown in Table 5, where "A" indicates EC ₅₀ <1μM, "B" indicates EC ₅₀ 1 μM and <10 μM, and “C” indicates EC ₅₀ 10 μM and <100 μM.

Example 189 NS5B inhibition analysis

The enzymatic activity of NS5B570-Con1 (Δ-21) was measured by incorporating deuterated NMP into the acid-insoluble RNA product. The complementary IRES (Cires) RNA sequence was used as a template corresponding to 377 nucleotides from the 3' end of the HCV (-) strand of the Con-1 strain, with a base content of 21% Ade, 23% Ura, 28 % Cyt and 28% Gua. Cires RNA was transcribed in vitro using the T7 transcriptome (Ambion, Inc.) and purified using the Qiagen Rneasy maxi kit. The HCV polymerase reaction contained 50 Nm NS5B570-Con1, 50 Nm Cires RNA, about 0.5 μCi deuterated NTP, 1 Mm competition cold NTP, 20 Mm NaCl, 40 Mm Tris-HCl (Ph 8.0), 4 Mm dithiothreitol, and 4 Mm MgCl ₂ . Standard reactions were incubated for 2 hours at 37 ° C in the presence of increasing concentrations of inhibitor. At the end of the reaction, RNA was precipitated with 10% TCA and the acid insoluble RNA product was filtered on a size exclusion 96 well plate. After washing the plates, scintillation fluid was added and the radiolabeled RNA product was detected using a Trilux Topcount scintillation counter according to standard procedures. The data was fitted by nonlinear regression (S-shaped) to calculate the enzymatic rate is reduced by 50% in which the compound concentration (IC _50).

Several independent experiments from an average value of the IC ₅₀ value is derived and shown in Table 6. The compounds of formula (I) and (II) are active in this assay. The value of "A" in the table below indicates IC ₅₀ <1μM, and the value of "B" indicates IC _50. 1μM and <10μM, and the value of “C” indicates the IC ₅₀ value 10 μM and <100 μM.

Example 190 Cell-based dengue virus analysis

Type 2 dengue virus strain New Guniea C (NG-C) and type 4 dengue virus strain H241 were purchased from ATCC (Manassas, VA; item numbers VR-1584 and VR-1490, respectively). 24 hours prior to the administration, Huh-7.5 cells / mL density of 1.5 × 10 ⁵ seeded in DMEM medium in 96-well plates in medium supplemented with 10% fetal calf serum, 1% HEPES buffer, 1% penicillin / Streptomycin and 1% non-essential amino acid (both Mediatech, Manassas, VA). On the day of infection, serially diluted compounds were added to the cells and incubated for 4 hours. After the end of the 4 hour pre-incubation period, cells were infected with type 2 dengue virus NG-C or type 4 dengue virus H241. The selection of the virus inoculum caused an 80-90% cytopathic effect within five to six days. The infected cells were incubated at five (NG-C) to six (H241) days at 37 ° C, 5% CO ₂ . For analysis, 100 μL of medium was changed to 100 μL of CellTiter-Glo® reagent (Promega, Madison, WI) and incubated for 10 minutes at room temperature. Luminescence was measured on a Victor X3 multi-label reader. Potential compound cytotoxicity was determined using uninfected parallel cultures.

The compounds of formula (I) and (II) are active in this assay. The antiviral activity of the exemplified compounds is shown in Table 7, wherein the A value of "A" in the following table indicates IC ₅₀ < 1 μM, the B value of "B" indicates IC ₅₀ < 10 μM, and the C value of "C" indicates IC. ₅₀ value <100 μM.

Example 191 Dengue virus polymerase inhibition assay

The enzymatic activity of the dengue virus NS5 polymerase domain (DENVpol, serotype 2, New Guinea C strain) was measured by incorporation of deuterated NMP in the acid-insoluble RNA product. The DENVpol assay reaction contained 100 nM recombinase, 50 nM heteropolymer RNA, about 0.5 μCi deuterated NTP, 0.33 μM competing cold NTP, 40 mM HEPES (pH 7.5), 3 mM dithiothreitol, and 2 mM MgCl ₂ . Standard reactions were incubated for 3 hours at 30 ° C in the presence of increasing concentrations of inhibitor. At the end of the reaction, RNA was precipitated with 10% TCA and the acid insoluble RNA product was filtered on a size exclusion 96 well plate. After washing the plates, scintillation fluid was added and the radiolabeled RNA product was detected using a Trilux Topcount scintillation counter according to standard procedures. The data was fitted by nonlinear regression (S-shaped) to calculate the enzymatic rate is reduced by 50% in which the compound concentration (IC _50).

Several independent experiments from an average value of the IC ₅₀ value is derived and shown in Table 8. The compound of formula (I) exhibits activity in this assay. The "A" value in the table below indicates IC ₅₀ <1 μM, the value of "B" indicates IC ₅₀ <10 μM, and the value of "C" indicates that the IC ₅₀ value is <100 μM.

Example 192 Cell-based flavivirus immunity (CFI) analysis

BHK21 or A549 cells were trypsinized, counted and diluted to 2×10 ⁵ cells per ml in Hams F-12 medium (for A549 cells) or RPMI-1640 medium (for BHK21 cells), supplemented with 2% fetal medium. Bovine serum and 1% penicillin/streptomycin. 2 x 10 ⁴ cells were dispensed into each well of a 96-well tissue culture plate and placed at 37 ° C under 5% CO ₂ overnight. On the next day, the cells were infected with the virus for 1 hour at 37 ° C and 5% CO ₂ in the same medium in the presence of varying concentrations of the test compound at an infection magnification (MOI) of 0.3. The medium containing the virus and the compound was removed, replaced with fresh medium containing only the test compound and incubated for an additional 48 hours at 37 ° C, 5% CO ₂ . The cells were washed once with PBS and fixed with cold methanol for 10 minutes. After washing twice with PBS, the cells were blocked with PBS containing 1% FBS and 0.05% Tween-20 for 1 hour at room temperature. A primary antibody solution (4G2) at a concentration of 1:20 to 1:100 in PBS containing 1% FBS and 0.05% Tween-20 was then added for 3 hours. The cells were then washed three times with PBS and then incubated with horseradish peroxidase (HRP)-conjugated anti-mouse IgG (Sigma, 1:2000 dilution) for 1 hour. After washing three times with PBS, 50 μL of 3,3',5,5'-tetramethylbenzidine (TMB) substrate (Sigma) was added to each well for 2 minutes. The reaction was stopped by the addition of 0.5 M sulfuric acid. Plates were read at 450 nm absorbance for viral load quantification. After the measurement, the cells were washed 3 times with PBS, followed by incubation with propidium iodide for 5 minutes. Plates were read for Teca Safire plate reader (excitation 537 nm, emission 617 nm) for cell number quantification. A dose response curve is plotted from the log of the average absorbance relative to the concentration of the test compound. By nonlinear regression analysis to calculate EC _50. A positive control such as N-mercapto-deoxynojirimycin can be used.

Example 193 Cell-based flavivirus cytopathic effect (CPE) analysis

For testing West Nile virus or Japanese encephalitis virus, BHK21 cells were trypsinized and diluted to RPMI-1640 medium to a concentration of 4×10 ⁵ cells/mL supplemented with 2% fetal bovine serum and 1 % penicillin / streptomycin. In order to test the dengue virus, the Huh7 cells were trypsinized and diluted to a concentration of 4 × 10 ⁵ cells / mL in the DMEM medium supplemented with 5% fetal calf serum and 1% penicillin / streptomycin. 50 μL of cell suspension (2 × 10 ⁴ cells) was dispensed per well in a 96-well optical bottom PIT polymerase plate (Nunc). The cells were grown overnight in culture medium at 37 ° C, 5% CO ₂ , followed by infection of West Nile virus (eg B956 strain) with MOI=0.3 or Japanese encephalitis virus (eg Zhongshan virus strain) in the presence of different concentrations of test compound (Nakayama strain), or a dengue virus (such as DEN-2 NGC strain) infected with MOI = 1. The plate containing the virus and the compound is further incubated at 37 ° C, 5% CO ₂ for 72 hours. At the end of the incubation, each well is 100 μL of CellTiter-Glo® reagent was added. The contents were mixed on an orbital shaker for 2 minutes to induce cell breakdown. The plates were incubated for 10 minutes at room temperature to stabilize the luminescence signal. The plate reader was used to record luminescence readings. Positive control, such as N-mercapto-deoxynojirimycin.

While the foregoing is described in detail, by reference to the claims Therefore, it is to be understood that the invention is not to be construed as limited

Claims (153)

Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for ameliorating or treating a viral infection, wherein the compound of formula (I) has the structure: Wherein: B ^1A is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having a protected amine group; --- is absent or is a single bond, and the limitation is Both -------- do not exist or both -------- are single keys; when -------- does not exist, then Z ¹ does not exist, O ¹ is OR ^1A , and R ^3A is selected from the group consisting of H, halo, OH, -OC(=O)R" ^A and optionally substituted O-linked amino acid, and R ^4A is selected from the following Group of constituents: H, OH, halo, N ₃ , -OC(=O)R" ^B , optionally substituted O-linked amino acid and NR" ^B1 R" ^B2 , or R ^3A and R ^4A To form a 5-membered ring oxygen atom via a carbonyl linkage; when -------- each is a single bond, then Z ¹ is , O ¹ is O, R ^3A is O; R ^4A is selected from the group consisting of H, OH, halo, N ₃ , -OC(=O)R" ^B , optionally substituted O-bonded amine a base acid and NR" ^B1 R"^B2; and R ^1B is selected from the group consisting of O ^- , OH, -O-, optionally substituted C _1-6 alkyl, And optionally substituted N-linked amino acids and optionally substituted N-linked amino acid ester derivatives; R ^a1 and R ^{a2 are} independently hydrogen or deuterium; R ^A is hydrogen, deuterium, unsubstituted C _1-3 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-3 alkynyl or cyano; R ^1A is selected from the group consisting of hydrogen, optionally substituted Sulfhydryl, optionally substituted O-linked amino acid, , and ; R ^2A is hydrogen, halo, unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, -CHF ₂ , -(CH _{2 1-6} halogen, -(CH ₂ ) _1-6 N ₃ , -(CH ₂ ) _1-6 NH ₂ or -CN; R ^5A is selected from the group consisting of H, halo, OH, optionally Substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; R ^6A , R ^7A and R ^8A are independently selected from the group consisting of Group: non-existent, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _{3 -6} cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl (C _1-6 alkyl ), optionally substituted by -(CR ^15A R ^16A ) _p -OC _1-24 alkyl, optionally substituted *-(CR ^17A R ^18A ) _q -OC _1-24 alkenyl, R ^6A is And R ^7A is absent or is hydrogen; or R ^6A and R ^7A are taken together to form a moiety selected from the group consisting of: as appropriate And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6A and R ^7A form a six to ten member ring system; the R ^9A system is independently selected from the group consisting of: optionally substituted C _1-24 alkyl, Substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, NR ^30A R ^31A , optionally substituted N-linked amino acid and optionally substituted N-bonded amino acid ester derivative; R ^10A and R ^{11A are} independently optionally substituted N-linked amino acids And optionally substituted N-linked amino acid ester derivatives; R ^12A and R ^{13A are} independently absent or hydrogen; R ^14A is O ^- , OH or methyl; each R ^15A , each R ^16A , each R ^17A and each R ^{18A are} independently hydrogen, optionally substituted C _1-24 alkyl or alkoxy; R ^19A , R ^20A , R ^22A , R ^23A , R ^2B , R ^3B , R ^5B and R ^6B are Independently selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^21A and R ^4B are independently selected from the group consisting of hydrogen, optionally the substituted C _1-24 alkyl group, as appropriate The substituted aryl, the optionally substituted -OC _1-24 alkyl, optionally substituted aryl group of -O-, optionally substituted aryl group and the -O- heteroaryl optionally substituted -O- of Monocyclic heterocyclic group; R ^24A and R ^7B are independently selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl, optionally substituted -O-monocyclic heterocyclyl and ; R ^25A , R ^26A , R ^29A , R ^8B and R ^9B are independently selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^27A1 and R ^27A2 is independently selected from the group consisting of ^-C≡N , optionally substituted C _2-8 organic carbonyl, optionally substituted C _2-8 alkoxycarbonyl, and optionally substituted C _{2 -8organidoaminocarbonyl} ; R ^28A is selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkenyl; R ^30A and R ^31A are independently selected from the group consisting of hydrogen, Substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C _3-6 cycloalkenyl and optionally substituted aryl (C _1-4 alkyl); R" ^A and each R" ^{B are,} independently, optionally substituted C _1-24 alkyl; Each R" ^B1 and each R" ^{B2 is} independently hydrogen and optionally substituted C _1-6 alkane m; v and w are 0 or 1; p and q are independently 1, 2 or 3; r and s are independently 0, 1, 2 or 3; t is 1 or 2; u and y are independently Is 3, 4 or 5; and Z ^1A , Z ^2A , Z ^3A , Z ^4A , Z ^1B and Z ^{2B are} independently O or S; wherein the viral infection is selected from the group consisting of Picornaviridae virus and yellow a virus caused by a group of viruses of the family Flaviviridae ; and a limitation thereof, if the virus of the Flaviviridae is a hepatitis C virus, the compound of the formula (I) or a pharmaceutically acceptable salt thereof cannot be selected from the following Group of groups: , or a pharmaceutically acceptable salt thereof. The use of claim 1, wherein the virus is a member of the picornavirus family of viruses. The use of claim 2, wherein the picornavirus family is selected from the group consisting of: Aphthovirus, Enterovirus, Rhinovirus, Hepatovirus, and Double Aco Virus (Parechovirus). The use of claim 3, wherein the enterovirus is selected from the group consisting of enterovirus A, enterovirus B, enterovirus C, enterovirus D, enterovirus E, enterovirus F, enterovirus G, enterovirus H And enterovirus J. The use of claim 3, wherein the enterovirus is selected from the group consisting of poliovirus 1 , poliovirus 2, poliovirus 3, CV-A1, CV- A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8, CV-A9, CV-A10, CV-A11, CV-A12, CV-A13, CV-A14, CV-A15, CV-A16, CV-A17, CV-A18, CV-A19, CV-A20, CV-A21, CV-A22, CV-A23, CV-B1, CV-B2 CV-B3, CV-B4, CV-B5, CV-B6, echovirus 1, echovirus 2, echovirus 3, echovirus 4, echovirus 5, echovirus 6, Echovirus 7, Echovirus 9, Echovirus 11, Echovirus 12, Echovirus 13, Echovirus 14, Echovirus 15, Echovirus 16, Echovirus 17, Echovirus 18, Echovirus 19, Echovirus 20, Echovirus 21, Echovirus 24, Echovirus 25, Echovirus 26, Echovirus 27, Echovirus 29, Echovirus 30, Echovirus 31, Echovirus 32, Echovirus 33, Echovirus 68, Echovirus 69, Echovirus 70, Echovirus 71 and Viruis human encephalomyelitis virus. The use of claim 3, wherein the enterovirus is selected from the group consisting of rhinovirus A, rhinovirus B, and rhinovirus C. The use of claim 3, wherein the hepatic virus is hepatitis A. The use of claim 3, wherein the bis-virus is selected from the group consisting of: human bis-virus, human ecclesiavirus 2, human bis-virus, human bis-virus, human Double Echovirus 5 and human double Echovirus 6. The use of claim 2, wherein the picornavirus family is selected from the group consisting of Aquamavirus, Avihepatovirus, Cardiovirus, and Coxsackie Genus (Cosavirus), Dicipivirus, Erbovirus, Kobuvirus, Megrivirus, Salivirus, Sapolovirus (Sapelovirus), Senecavirus, Teschovirus, and Tremovirus. The use of claim 1, wherein the virus is a Flaviviridae virus. The use of claim 10, wherein the Flaviviridae virus is selected from the group consisting of Flavivirus, Hepacirus, and Prion (Pestivirus). The use of claim 10, wherein the Flaviviridae virus is selected from the group consisting of hepatitis C virus (HCV), yellow fever virus (YFV), West Nile virus (WNV), and dengue virus ( Dengue fever virus), encephalitis virus in the Flaviviridae, classic swine fever virus, and bovine diarrhea virus. The use of claim 12, wherein the encephalitis virus in the Flaviviridae is selected from the group consisting of Japanese encephalitis virus (JEV) and tick-borne encephalitis virus (tick-borne encephalitis virus). TBEV). The use of any one of claims 1 to 13, wherein R ^2A is hydrogen. The use of any one of claims 1 to 13, wherein R ^2A is a halogen group. The use of claim 15, wherein the halide is fluorine. The use of any one of claims 1 to 13, wherein R ^2A is an unsubstituted C _1-4 alkyl group. The use of any one of claims 1 to 13, wherein R ^2A is an unsubstituted C _2-4 alkenyl group. The use of any one of claims 1 to 13, wherein R ^2A is an unsubstituted C _2-4 alkynyl group. The use of any one of claims 1 to 13, wherein R ^2A is -CHF ₂ . The use of any one of claims 1 to 13, wherein R ^2A is -(CH ₂ ) _1-6 halogen. The use of any one of claims 1 to 13, wherein R ^2A is -(CH ₂ ) _1-6 F. The use of any one of claims 1 to 13, wherein R ^2A is -(CH ₂ ) _1-6 Cl. The use of any one of claims 1 to 13, wherein R ^2A is -(CH ₂ ) _1-6 N ₃ . The use of any one of claims 1 to 13, wherein R ^2A is -(CH ₂ ) _1-6 NH ₂ . The use of any one of claims 1 to 13, wherein R ^2A is -CN. The use of any one of claims 1 to 25, wherein R ^4A is H. The use of any one of claims 1 to 25, wherein R ^4A is OH. The use of any one of claims 1 to 25, wherein R ^4A is a halo group. The use of claim 29, wherein the halide group is F. The use of claim 29, wherein the halide is Cl. The use of any one of claims 1 to 25, wherein R ^4A is -OC(=O)R" ^B or optionally substituted O-linked amino acid. The use of any one of claims 1 to 25, wherein R ^4A is N ₃ or NR" ^B1 R" ^B2 . The use of any one of claims 1 to 33, wherein R ^5A is H. The use of any one of claims 1 to 33, wherein R ^5A is a halo group. The use of any one of claims 1 to 33, wherein R ^5A is OH. The use of any one of claims 1 to 33, wherein R ^5A is optionally substituted C _1-6 alkyl. The use of any one of claims 1 to 33, wherein R ^5A is optionally substituted C _2-6 alkenyl. The use of any one of claims 1 to 33, wherein R ^5A is optionally substituted C _2-6 alkynyl. The use of any one of claims 1 to 39, wherein ------- is absent. The use of any one of claims 1 to 40, wherein R ^1A is hydrogen. The use of any one of claims 1 to 40, wherein R ^1A is an optionally substituted thiol or an optionally substituted O-linked amino acid. The use of any one of claims 1 to 40, wherein R ^1A is . The use of claim 43, wherein R ^6A is R ^7A is absent or hydrogen and m is 0. The use of claim 43, wherein R ^6A is R ^7A is absent or hydrogen and m is 1. The use of claim 43, wherein R ^6A and R ^{7A are} independently absent or hydrogen. The use of claim 43, wherein R ^6A and R ^{7A are,} independently, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkyne Substituted, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted Aryl (C _1-6 alkyl). The use of claim 43, wherein R ^6A and R ^{7A are} independently optionally substituted *-(CR ^15A R ^16A ) _p -OC _1-24 alkyl or optionally substituted *-(CR ^17A R ^18A _q- OC _1-24 alkenyl. The use of claim 43, wherein R ^6A and R ^{7A are} independently , The use of claim 43, wherein R ^6A and R ^{7A are} independently The use of claim 43, wherein R ^6A and R ^7A are taken together to form a moiety selected from the group consisting of: And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6A and R ^7A form a six to ten member ring system. The use of any one of claims 43 to 51, wherein Z ^1A is O. The use of any one of claims 43 to 51, wherein Z ^1A is S. The use of any one of claims 1 to 43 wherein R ^1A is . The use of claim 54, wherein R ^8A is an optionally substituted aryl group. The use of claim 54, wherein R ^8A is optionally substituted heteroaryl. The use according to any one of claims 54 to 56, wherein R ^9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. The use of claim 57, wherein R ^9A is Wherein R ^33A is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted aryl, optionally Substituted aryl (C _1-6 alkyl) and optionally substituted haloalkyl; R ^34A is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C ₆ aryl, optionally substituted C ₁₀ aryl, and optionally substituted aryl ( C _1-6 alkyl); and R ^35A is hydrogen or optionally substituted C _1-4 alkyl; or R ^34A and R ^35A are taken together to form an optionally substituted C _3-6 cycloalkyl. The use of claim 57, wherein R ^9A is selected from the group consisting of: The use of any one of claims 54 to 59, wherein Z ^2A is O. The use of any one of claims 54 to 59, wherein Z ^2A is S. The use of any one of claims 1 to 40, wherein R ^1A is . The use of claim 62, wherein R ^10A and R ^{11A are,} independently, optionally substituted N-linked amino acids or optionally substituted N-linked amino acid ester derivatives. The compound of claim 62, wherein R ^10A and R ^{11A are} independently Wherein R ^36A is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted aryl, optionally Substituted aryl (C _1-6 alkyl) and optionally substituted haloalkyl; R ^37A is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C ₆ aryl, optionally substituted C ₁₀ aryl, and optionally substituted aryl ( C _1-6 alkyl); and R ^38A is hydrogen or optionally substituted C _1-4 alkyl; or R ^37A and R ^38A are taken together to form an optionally substituted C _3-6 cycloalkyl. The use of claim 64, wherein R ^10A and R ^11A are independently selected from the group consisting of: , , , The use of any one of claims 62 to 65, wherein Z ^3A is O. The use of any one of claims 62 to 65, wherein Z ^3A is S. The use of any one of claims 40 to 67, wherein R ^3A is H. The use of any one of claims 40 to 67, wherein R ^3A is a halo group. The use of claim 69, wherein the halide is fluorine. The use of claim 69, wherein the halide is chlorine. The use of any one of claims 40 to 67, wherein R ^3A is OH. The use of any one of claims 40 to 67, wherein R ^3A is -OC(=O)R" ^A or optionally substituted O-linked amino acid. The use of any one of claims 40 to 67, wherein R ^3A and R ^4A are each an oxygen atom bonded to form a 5-membered ring via a carbonyl group. The use of any one of claims 1 to 39, wherein -------- is each a single bond. The use of claim 75, wherein R ^1B is O ^- or OH. The use of claim 75, wherein R ^1B is -O- optionally substituted C _1-6 alkyl. The use of claim 75, wherein R ^1B is , And optionally substituted N-linked amino acids or optionally substituted N-linked amino acid ester derivatives. The use of any one of claims 1 to 78, wherein R ^A is hydrogen. The use of any one of claims 1 to 78, wherein R ^A is 氘. The use of any one of claims 1 to 78, wherein R ^A is an unsubstituted C _1-3 alkyl group. The use of any one of claims 1 to 78, wherein R ^A is an unsubstituted C _2-4 alkenyl group. The use of any one of claims 1 to 78, wherein R ^A is an unsubstituted C _2-3 alkynyl group. The use of any one of claims 1 to 78, wherein R ^A is cyano. The use of any one of claims 1 to 84, wherein R ^a1 and R ^a2 are both hydrogen. The use of any one of claims 1 to 84, wherein R ^a1 and R ^a2 are both 氘. The use of any one of claims 1 to 86, wherein the B ^1A is selected from the group consisting of: Wherein: R ^A2 is selected from the group consisting of hydrogen, halogen and NHR ^J2 , wherein R ^J2 is selected from the group consisting of hydrogen, -C(=O)R ^K2 and -C(=O)OR ^L2 ; R ^B2 is halogen or NHR ^W2 , wherein R ^W2 is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _3-8 cycloalkyl, -C(=O)R ^M2 and -C(=O)OR ^N2 ; R ^C2 is hydrogen or NHR ^O2 , wherein R ^O2 is selected from the group consisting of hydrogen, -C ( =O)R ^P2 and -C(=O)OR ^Q2 ; R ^D2 is selected from the group consisting of hydrogen, deuterium, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _{2 -6} alkenyl and optionally substituted C _2-6 alkynyl; R ^E2 is selected from the group consisting of hydrogen, hydroxy, optionally substituted C _1-6 alkyl, optionally substituted C _{3 -8} cycloalkyl, -C(=O)R ^R2 and -C(=O)OR ^S2 ; R ^F2 is selected from the group consisting of hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl group and the optionally substituted C _2-6 alkynyl group of; Y ² and Y ³ are independently N or CR ^I2, wherein R ^I2 group selected from the group consisting of The group: hydrogen, halo, optionally substituted alkyl of C _1-6, optionally substituted C _2-6 alkenyl group and the optionally substituted C _2-6 alkynyl group of; W ¹ is NH, -NCH ₂ -OC(=O)CH(NH ₂ )-CH(CH ₃ ) ₂ or -(CH ₂ ) _1-2 -OP(=O)(OW ^1A ) ₂ , wherein W ^1A is selected from the group consisting of : a C _1-6 alkyl group which is absent, hydrogen and optionally substituted; R ^G2 is optionally substituted C _1-6 alkyl; R ^H2 is hydrogen or NHR ^T2 , wherein R ^{T2 is} independently selected from the group consisting of Groups: hydrogen, -C(=O)R ^U2 and -C(=O)OR ^V2 ; and R ^K2 , R ^L2 , R ^M2 , R ^N2 , R ^P2 , R ^Q2 , R ^R2 , R ^S2 , R ^U2 And R ^V2 are independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenene , C _6-10 aryl, heteroaryl, heterocyclic, aryl (C _1-6 alkyl), heteroaryl (C _1-6 alkyl) and heterocyclic (C _1-6 alkyl) ). The use of claim 87, wherein B ^1A is . The use of claim 87, wherein B ^1A is . The use of claim 87, wherein B ^1A is . The use of claim 87, wherein B ^1A is . The use of claim 87, wherein B ^1A is . The use of claim 87, wherein B ^1A is . The use of claim 1, wherein the compound is selected from the group consisting of: and , or a pharmaceutically acceptable salt thereof. The use of claim 1, wherein the compound is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof. The use of claim 1, wherein the compound is selected from the group consisting of: and , or a pharmaceutically acceptable salt thereof. A compound of the formula (II) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (II) has the following structure: Wherein: B ^1C is optionally substituted heterocyclic base or optionally substituted heterocyclic base having a protected amine group; -------- is absent or is a single bond, the limitation is Both -------- do not exist or both -------- are single keys; when -------- does not exist, then Z ² does not exist, O ² is OR ^1C , and R ^3C is selected from the group consisting of H, halo, OH, -OC(=O)R" ^C and optionally substituted O-linked amino acid, and R ^4C is selected from the following Group of constituents: H, OH, halo, N ₃ , -OC(=O)R" ^D , optionally substituted O-linked amino acid and NR" ^D1 R" ^D2 , or R ^3C and R ^4C To form a 5-membered ring oxygen atom via a carbonyl linkage; when -------- each is a single bond, then Z ² is O ² is O, R ^3C is O; R ^4C is selected from the group consisting of OH, halo, N ₃ , -OC(=O)R" ^D , optionally substituted O-linked amino acid And NR" ^D1 R"^D2; and R ^1D are selected from the group consisting of O ^- , OH, -O-, optionally substituted C _1-6 alkyl, And optionally substituted N-linked amino acids and optionally substituted N-linked amino acid ester derivatives; R ^c1 and R ^{c2 are} independently hydrogen or deuterium; R ^C is hydrogen, deuterium, unsubstituted C _1-3 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-3 alkynyl or cyano; R ^1C is selected from the group consisting of hydrogen, optionally substituted Sulfhydryl, optionally substituted O-linked amino acid, , and ; R ^2C is hydrogen, halo, unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, -CHF ₂ , -(CH _{2 1-6} halogen, -(CH ₂ ) _1-6 N ₃ , -(CH ₂ ) _1-6 NH ₂ or -CN; R ^5C is selected from the group consisting of H, halo, OH, optionally Substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, and optionally substituted C _2-6 alkynyl; R ^6C , R ^7C and R ^8C are independently selected from the group consisting of Group: non-existent, hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _{3 -6} cycloalkyl, optionally substituted C _3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl (C _1-6 alkyl ), optionally substituted by -(CR ^15C R ^16C ) _f -OC _1-24 alkyl, optionally substituted *-(CR ^17C R ^18C ) _g -OC _1-24 alkenyl, R ^6C is And R ^7C is absent or is hydrogen; or R ^6C and R ^7C are taken together to form a moiety selected from the group consisting of: And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6C and R ^7C form a six to ten member ring system; the R ^9C is independently selected from the group consisting of C _1-24 alkyl optionally substituted Substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkenyl, NR ^30C R ^31C , optionally substituted N-linked amino acid and optionally substituted N-linked amino acid ester derivative; R ^10C and R ^{11C are} independently optionally substituted N-linked amino acids And optionally substituted N-linked amino acid ester derivatives; R ^12C and R ^{13C are} independently absent or hydrogen; R ^14C is O ^- , OH or methyl; each R ^15D , each R ^16C , each R ^17C and each R ^{18C are} independently hydrogen, optionally substituted C _1-24 alkyl or alkoxy; R ^19C , R ^20C , R ^22C , R ^23C , R ^2D , R ^3D , R ^5D and R ^6D are Independently selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^21C and R ^4D are independently selected from the group consisting of hydrogen, optionally the substituted C _1-24 alkyl group, as appropriate The substituted aryl, the optionally substituted -OC _1-24 alkyl, optionally substituted aryl group of -O-, optionally substituted aryl group and the -O- heteroaryl optionally substituted -O- of Monocyclic heterocyclic group; R ^24C and R ^7D are independently selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl, optionally substituted aryl, optionally substituted -OC _1-24 alkyl, optionally substituted -O-aryl, optionally substituted -O-heteroaryl, optionally substituted -O-monocyclic heterocyclyl and ; R ^25C , R ^26C , R ^29C , R ^8D and R ^9D are independently selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl and optionally substituted aryl; R ^27C1 and R ^27C2 is independently selected from the group consisting of ^-C≡N , optionally substituted C _2-8 organic carbonyl, optionally substituted C _2-8 alkoxycarbonyl, and optionally substituted C _{2 -8organidoaminocarbonyl} ; R ^28C is selected from the group consisting of hydrogen, optionally substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl and optionally substituted C _3-6 cycloalkenyl; R ^30C and R ^31C are independently selected from the group consisting of hydrogen, Substituted C _1-24 alkyl, optionally substituted C _2-24 alkenyl, optionally substituted C _2-24 alkynyl, optionally substituted C _3-6 cycloalkyl, optionally Substituted C _3-6 cycloalkenyl and optionally substituted aryl (C _1-4 alkyl); R" ^C and each R" ^{D are,} independently, optionally substituted C _1-24 alkyl; each R ^"D1 and each R" ^D2 are independently hydrogen or optionally substituted C _1-24 of Base; c, d and e are independently 0 or 1; f and g are independently 1, 2 or 3; h and j are independently 0, 1, 2 or 3; b is 1 or 2; k and l are independent The ground is 3, 4 or 5; and Z ^1C , Z ^2C , Z ^3C , Z ^4C , Z ^1D and Z ^{2D are} independently O or S; the limitation is when R ^2C is a halogen group; ----- --- None; Z ² is absent; O ² is OR ^1C ; B ^1C is selected from the group consisting of: Replace it as appropriate Replace it as appropriate Replace it as appropriate Replace it as appropriate And replaced by circumstances Wherein R ^a2 is optionally substituted C _1-6 alkyl or optionally substituted C _3-6 cycloalkyl, and R ^a3 and R ^a4 are independently selected from the group consisting of hydrogen, unsubstituted C _1-6 alkyl, unsubstituted C _3-6 alkenyl, unsubstituted C _3-6 alkynyl and unsubstituted C _3-6 cycloalkyl, R ^a5 is NHR ^a8 , and R ^A6 is hydrogen, halogen or NHR ^a9 ; R ^a7 is NHR ^a10 ; R ^a8 is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 alkenyl , optionally substituted C _3-6 cycloalkyl, -C(=O)R ^a11 and -C(=O)OR ^a12 ; R ^a9 is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 alkenyl, optionally substituted C _3-6 cycloalkyl, -C(=O)R ^a13 and -C(=O)OR ^a14 ;R ^A10 is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 alkenyl, optionally substituted C _3-6 cycloalkyl, -C (=O)R ^a15 and -C(=O)OR ^a16 ; X ^a1 is N or -CR ^a17 ; R ^a17 is selected from the group consisting of hydrogen, halogen, optionally substituted C _1-6 alkyl ,Subject to availability Substituted C _2-6 alkenyl and optionally substituted C _2-6 alkynyl; R ^a11 , R ^a12 , R ^a13 , R ^a14 , R ^a15 and R ^a16 are each independently selected from the group consisting of: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, heteroaryl, heterocyclic An aryl group (C _1-6 alkyl group), a heteroaryl group (C _1-6 alkyl group) and a heterocyclic group (C _1-6 alkyl group); wherein R ^3C is selected from the group consisting of H, halogen And an optionally substituted O-linked amino acid; and R ^4C is selected from the group consisting of OH, halo, N ₃ , -OC(=O)R" ^D , optionally substituted O bond Amino acid and NR" ^D1 R"^D2; or R ^3C is selected from the group consisting of H, halo, OH, -OC(=O)R" ^C and optionally substituted O-bonded amine a base acid and R ^4C is an optionally substituted O-linked amino acid; or R ^1C is Where R ^6C and R ^{7C are} independently Where h is 1, 2 or 3, or Or R ^1C is Wherein R ^6C and R ^7C are taken together to form a moiety selected from the group consisting of: as appropriate And replaced by circumstances Wherein the oxygen, phosphorus and the moiety attached to R ^6C and R ^7C form a six to ten member ring system; the restriction is when R ^2C is a halogen group; --- each is a single bond; Then R ^4C is -OC(=O)R" ^D or an optionally substituted O-bonded amino acid; the restriction is that when R ^2C is unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, -(CH ₂ ) _1-6 halogen, -(CH ₂ ) _1-6 N ₃ or -(CH ₂ ) _1-6 NH ₂ ;- ------- are absent; Z ² is absent; O ² is OR ^1C ; R ^3C is OH, -OC(=O)R" ^C or optionally substituted O-linked amino acid; When R ^4C is a halogen group; then R ^5C is selected from the group consisting of C _1-6 alkyl optionally substituted, optionally substituted C _2-6 alkenyl, and optionally substituted C _{2 - 6} alkynyl; the restriction is when R ^2C is unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl, -(CH ₂ ) _1-6 halogen, -(CH ₂ ) _1-6 N ₃ or -(CH ₂ ) _1-6 NH ₂ ;-------- are absent; Z ² is absent; O ² is OR ^1C ; R ^4C is a halogen group; and when R ^5C is H or a halogen group; then R ^3C is H or a halogen group; the restriction condition is when R ^2C is not Substituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl or -(CH ₂ ) _1-6 halogen; --- None exists; Z ² is absent; O ² is OR ^1C ; R ^3C is OH, -OC(=O)R" ^C or optionally substituted O-linked amino acid; R ^4C is halo; R ^5C Is H or a halogen group; and R ^1C is At least one of R ^6C and R ^7C is Wherein R ^{21C is} independently selected from the group consisting of -O-heteroaryl optionally substituted with O-monocyclic heterocyclyl optionally substituted; or at least one of R ^6C and R ^7C for Where s is 1, 2 or 3; or at least one of R ^6C and R ^7C is Wherein s is 0 and R ^24C is optionally substituted -O-heteroaryl or optionally substituted -O-monocyclic heterocyclyl; the limitation is when R ^2C is unsubstituted C _{1- 4-} alkyl, unsubstituted C _2-4 alkenyl, unsubstituted C _2-4 alkynyl or -(CH ₂ ) _1-6 halogen; --- none; Z ² It does not exist; O ² is oR ^1C; R ^3C is OH, -OC (= O) R "C or optionally substituted amino acid of the O-linked bond; R ^4C is a halogen group; R ^5C is H or halo; And R ^1C is Time; then R ^8C is Wherein R ^{21C is} independently selected from the group consisting of -O-heteroaryl optionally substituted with O-monocyclic heterocyclyl optionally substituted; or R ^8C is Where s is 1, 2 or 3; or R ^8C is Wherein s is 0 and R ^24C is optionally substituted -O-heteroaryl, optionally substituted -O-monocyclic heterocyclyl or The limitation is that when -------- is absent; Z ² is absent; O ² is OH; R ^2C is methyl; R ^3C is OH; then R ^4C is halo, -OC ( =O)R" ^D or optionally substituted O-linked amino acid; and its limitation is that when ------- is absent; Z ² is absent; O ² is OR ^1C ; R ^2C Is fluorine; R ^3C is OH or -OC(=O)R"^C; R ^4C is fluorine; and R ^5C is methyl, ethyl or vinyl; then R ^1C cannot be selected from the group consisting of: H, and Wherein R ^8C is an unsubstituted aryl group; R ^9C is And Z ^2C is oxygen. The compound of claim 97, wherein R ^2C is hydrogen. The compound of claim 97, wherein R ^2C is halo. The compound of claim 99, wherein the halide is fluorine. The compound of claim 97, wherein R ^2C is unsubstituted C _1-4 alkyl. The compound of claim 97, wherein R ^2C is unsubstituted C _2-4 alkenyl. The compound of claim 97, wherein R ^2C is unsubstituted C _2-4 alkynyl. The compound of claim 97, wherein R ^2D is -CHF ₂ . The compound of claim 97, wherein R ^2C is -(CH ₂ ) _1-6 halogen. The compound of claim 97, wherein R ^2C is -(CH ₂ ) _1-6 F. The compound of claim 97, wherein R ^2C is -(CH ₂ ) _1-6 Cl. The compound of claim 97, wherein R ^2C is -(CH ₂ ) _1-6 N ₃ . The compound of claim 97, wherein R ^2C is -(CH ₂ ) _1-6 NH ₂ . The compound of claim 97, wherein R ^2C is -CN. The compound of claim 97, wherein R ^4C is H. The compound of any one of claims 97 to 111, wherein ------- is absent. The compound of claim 112, wherein R ^3C is halo. The compound of claim 113, wherein the halide is F. The compound of claim 113, wherein the halide is Cl. The compound of claim 112, wherein R ^3C is H. The compound of any one of claims 112 to 116, wherein R ^4C is H. The compound of any one of claims 112 to 116, wherein R ^4C is a halo group. The compound of claim 118, wherein the halide is fluorine. The compound of any one of claims 112 to 116, wherein R ^4C is OH. The compound of any one of claims 112 to 116, wherein R ^4C is -OC(=O)R" ^D or an optionally substituted O-linked amino acid. The compound of any one of claims 112 to 116, wherein R ^4C is N ₃ or NR" ^D1 R" ^D2 . A compound of claim 122, wherein NH _{2 is} . The compound of any one of claims 97 to 111, wherein --- each is a single bond. The compound of claim 124, wherein R ^1D is -O- optionally substituted C _1-6 alkyl. The compound of any one of claims 97 to 125, wherein R ^5C is H. The compound of any one of claims 97 to 125, wherein R ^5C is a halogen group. The compound of any one of claims 97 to 125, wherein R ^5C is OH. The compound of any one of claims 97 to 125, wherein R ^5C is optionally substituted C _1-6 alkyl. The compound of any one of claims 97 to 125, wherein R ^5C is optionally substituted C _2-6 alkenyl. The compound of any one of claims 97 to 125, wherein R ^5C is an optionally substituted C _2-6 alkynyl group. The compound of any one of claims 97 to 131, wherein R ^C is hydrogen. The compound of any one of claims 97 to 131, wherein R ^C is hydrazine. The compound of any one of claims 97 to 131, wherein R ^C is an unsubstituted C _1-3 alkyl group. The compound of any one of claims 97 to 131, wherein R ^C is an unsubstituted C _2-4 alkenyl group. The compound of any one of claims 97 to 131, wherein R ^C is an unsubstituted C _2-3 alkynyl group. The compound of any one of claims 97 to 131, wherein R ^C is cyano. The compound of any one of claims 97 to 137, wherein R ^c1 and R ^c2 are both hydrogen. The compound of any one of claims 97 to 137, wherein R ^c1 and R ^c2 are both hydrazine. The compound of any one of claims 97 to 139, wherein the B ^1C is selected from the group consisting of: Wherein: R ^AA2 is selected from the group consisting of hydrogen, halogen and NHR ^JJ2 , wherein R ^JJ2 is selected from the group consisting of hydrogen, -C(=O)R ^KK2 and -C(=O)OR ^LL2 ; R ^BB2 is halogen or NHR ^WW2 , wherein R ^WW2 is selected from the group consisting of hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _3-8 cycloalkyl, -C(=O)R ^MM2 and -C(=O)OR ^NN2 ; R ^CC2 is hydrogen or NHR ^OO2 , wherein R ^O2 is selected from the group consisting of hydrogen, -C ( =O)R ^PP2 and -C(=O)OR ^QQ2 ; R ^DD2 is selected from the group consisting of hydrogen, deuterium, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _{2 -6} alkenyl and optionally substituted C _2-6 alkynyl; R ^{EE 2} is selected from the group consisting of hydrogen, hydroxy, optionally substituted C _1-6 alkyl, optionally substituted C _{3 -8} cycloalkyl, -C(=O)R ^RR2 and -C(=O)OR ^SS2 ; R ^FF2 is selected from the group consisting of hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl group and the optionally substituted C _2-6 alkynyl group of; Y ⁴ and Y ⁵ are independently N or CR ^II2, wherein R ^II2 Is selected from the group consisting of: hydrogen, halogen, optionally substituted alkyl of C _1-6, optionally substituted C _2-6 alkenyl group and the optionally substituted C _2-6 alkynyl group of; W ² is NH, -NCH ₂ -OC(=O)CH(NH ₂ )-CH(CH ₃ ) ₂ or -(CH ₂ ) _1-2 -OP(=O)(OW ^2C ) ₂ , wherein W ^2C is selected from a group consisting of: non-existent, hydrogen and optionally substituted C _1-6 alkyl; R ^GG2 is optionally substituted C _1-6 alkyl; R ^{HH 2} is hydrogen or NHR ^TT2 wherein R ^TT2 is independent The ground is selected from the group consisting of hydrogen, -C(=O)R ^UU2 and -C(=O)OR ^VV2 ; and R ^KK2 , R ^LL2 , R ^MM2 , R ^NN2 , R ^PP2 , R ^QQ2 , R ^RR2 , R ^SS2 , R ^UU2 and R ^VV2 are independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _6-10 aryl, heteroaryl, heterocyclic, aryl (C _1-6 alkyl), heteroaryl (C _1-6 alkyl) and heterocyclic (C) _1-6 alkyl). The compound of claim 140, wherein B ^1C is . The compound of claim 140, wherein B ^1C is . The compound of claim 140, wherein B ^1C is . The compound of claim 140, wherein B ^1C is . The compound of claim 140, wherein B ^1C is . The compound of claim 140, wherein B ^1C is . A compound selected from the group consisting of: and Or a pharmaceutically acceptable salt thereof. A compound selected from the group consisting of: and , or a pharmaceutically acceptable salt thereof. A compound selected from the group consisting of: and , or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 97 to 149, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination. Use of a compound according to any one of claims 97 to 149 for the preparation of an agent for ameliorating or treating an HCV infection, wherein the agent is produced in combination with one or more agents selected from the group consisting of : interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (AA), compound of formula (BB) and compound of formula (CC) or a compound of the foregoing A pharmaceutically acceptable salt of either. Use of a compound according to any one of claims 97 to 149 for the preparation of a medicament for contacting a cell infected with a hepatitis C virus, wherein the medicament is produced with one or more selected from the group consisting of Combination of agents: interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (AA), compound of formula (BB) and compound of formula (CC) or the aforementioned compound A pharmaceutically acceptable salt of either of them. The use of any one of claims 151 to 152, wherein the one or more agents are selected from the group consisting of: compounds 1001-1016, 2001-2012, 3001-3014, 4001-4012, 5001-5011, 6001- 6078, 7000-7027 and 8000-8016, or a pharmaceutically acceptable salt of any of the foregoing compounds.